KR102545412B1 - Vaccine Composition for SFTS virus - Google Patents
Vaccine Composition for SFTS virus Download PDFInfo
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- KR102545412B1 KR102545412B1 KR1020200122298A KR20200122298A KR102545412B1 KR 102545412 B1 KR102545412 B1 KR 102545412B1 KR 1020200122298 A KR1020200122298 A KR 1020200122298A KR 20200122298 A KR20200122298 A KR 20200122298A KR 102545412 B1 KR102545412 B1 KR 102545412B1
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- South Korea
- Prior art keywords
- ser
- gly
- val
- lys
- leu
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Abstract
본 발명은 SFTS 바이러스의 Gn 또는 Gc 단백질의 세포외 도메인(extracellular domain)이 사람 항체 Fc 부위에 융합된 재조합 단백질, NP 단백질(전장 서열의 단백질) 또는 이들의 혼합물이 제1형 인터페론 수용체 KO 생쥐에서 보호면역을 제공하는 실험 결과에 기초하여 Gn 또는 Gc 단백질이나 NP 단백질 또는 이들의 혼합물을 이용한 SFTS 바이러스에 대한 백신 조성물을 개시한다.The present invention is a recombinant protein in which the extracellular domain of the Gn or Gc protein of the SFTS virus is fused to the Fc region of a human antibody, NP protein (protein of full-length sequence), or a mixture thereof in type 1 interferon receptor KO mice. A vaccine composition against SFTS virus using Gn or Gc protein or NP protein or a mixture thereof based on the experimental results providing protective immunity is disclosed.
Description
본 발명은 중증열성혈소판감소증후증 바이러스에 대한 백신 조성물에 대한 백신 조성물에 대한 것이다.The present invention relates to a vaccine composition for a vaccine composition against severe fever with thrombocytopenia syndrome virus.
중증열성혈소판감소증후증(Severe fever with thrombocytopenia syndrome, SFTS)은 SFTS virus(SFTSV) 감염에 의해 발생하는 감염질환이다. 2009년 중국에서 처음 보고된 이후로 중국, 한국, 일본, 베트남 등 아시아 국가들에서 발생이 보고되고 있다. SFTSV는 3개의 분절 RNA를 유전체로 보유하고 있으며, 각각 RNA 중합효소 (RdRp), 2개의 외막 당단백질(Gn, Gc), 그리고 뉴클레오캡시드(NP) 및 비구조단백질(NS)를 암호화하고 있다. 이 바이러스에 감염되면, 고열, 위장관 합병증, 백혈구 감소증, 혈소판 감소증을 동반하며, 치사율은 5~20%로 알려져 있다(Lancet Infect Dis 2018, 18, 1127-1137, doi:10.1016/S1473-3099(18)30293-7). 아직까지 치료제가 없으며, 백신 개발이 진행되고 있다.Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease caused by infection with the SFTS virus (SFTSV). Since it was first reported in China in 2009, outbreaks have been reported in Asian countries such as China, Korea, Japan, and Vietnam. SFTSV has three segmented RNAs in its genome, each encoding an RNA polymerase (RdRp), two outer membrane glycoproteins (Gn, Gc), and a nucleocapsid (NP) and non-structural protein (NS). Infection with this virus is accompanied by high fever, gastrointestinal complications, leukopenia, and thrombocytopenia, and the mortality rate is known to be 5 to 20% ( Lancet Infect Dis 2018, 18 , 1127-1137, doi:10.1016/S1473-3099(18 )30293-7). There is no cure yet, and vaccine development is ongoing.
SFTS 백신 개발은 초기 연구단계에 있으며, 최근 보고를 통해 재조합 바이러스 벡터를 이용한 백신이나 DNA 백신이 감염동물 모델에서 보호면역을 제공할 수 있다는 사실들이 확인되었다(NPJ Vaccines 2019, 4, 5, doi:10.1038/s41541-018-0096-y; Nat Commun 2019, 10, 3836, doi:10.1038/s41467-019-11815-4). NS 단백질을 이용한 백신은 항체 생성이 유도됨을 확인하였으나, 생쥐감염모델에서 보호면역을 제공하지 못하였다(Viral Immunol 2015, 28, 113-122, doi:10.1089/vim.2014.0100). NP와 NS 유전자를 암호화하는 DNA를 마이크로니들을 이용하여 면역하였을 때, 이 항원들에 특이적인 T 세포 반응이 유도된다는 사실도 보고되었으나, 동물감염 모델에서 보호면역을 제공하는지는 밝혀지지 않았다(Colloids Surf B Biointerfaces 2017, 159, 54-61, doi:10.1016/j.colsurfb.2017.07.059). 최근에 와서 Gn과 Gc 단백질을 발현하는 재조합 바이러스(live attenuated recombinant vesicular stomatitis virus, rVSV)를 1회 면역하였을 때, 중화항체 생성를 유도할 수 있으며, SFTSV가 치사량으로 감염된 제1형 인터페론 수용체 knock-out (KO) 생쥐에서 완벽한 보호면역을 유도한다는 논문이 보고되었다(NPJ Vaccines 2019, 4, 5, doi:10.1038/s41541-018-0096-y). 또한 SFTSV의 5개 유전자를 각각 발현하는 DNA를 같이 면역하였을 때, Gn 및 Gc를 암호화하는 DNA 두가지를 동시에 면역하였을 때, 그리고 NP, NS, RdRp를 암호화하는 세가지 DNA를 함께 면역하였을 때, SFTSV에 감수성이 있는 나이든 족제비(4년 이상)에서 치사감염에 대한 보호면역이 제공된다는 사실도 보고되었다(Nat Commun 2019, 10, 3836, doi:10.1038/s41467-019-11815-4). 그러나 아직까지 각각의 구조 단백질 (Gn, Gc, NP)을 개별 면역하였을 때, 어느 정도의 보호면역이 제공되는 지 보고된 바는 없으며, 이 단백질들을 이용한 아단위 단백질 백신의 효능에 관한 연구는 발표되지 않고 있다.SFTS vaccine development is in the early research stage, and recent reports have confirmed that vaccines using recombinant viral vectors or DNA vaccines can provide protective immunity in infected animal models ( NPJ Vaccines 2019, 4, 5, doi :10.1038/s41541-018-0096-y; Nat Commun 2019, 10, 3836, doi:10.1038/s41467-019-11815-4). It was confirmed that the vaccine using the NS protein induced antibody production, but failed to provide protective immunity in a mouse infection model ( Viral Immunol 2015, 28, 113-122, doi: 10.1089/vim.2014.0100). It has also been reported that immunization with DNA encoding NP and NS genes using a microneedle induces a T cell response specific to these antigens, but it has not been clarified whether protective immunity is provided in animal infection models ( Colloids Surf B Biointerfaces 2017, 159, 54-61, doi:10.1016/j.colsurfb.2017.07.059). Recently, once immunized with live attenuated recombinant vesicular stomatitis virus (rVSV) expressing Gn and Gc proteins, neutralizing antibody production can be induced, and SFTSV-infected
본 발명은 Gn 단백질, Gc 단백질, NP 단백질의 백신 효능을 개시한다.The present invention discloses the vaccine efficacy of Gn protein, Gc protein and NP protein.
본 발명의 목적은 Gn 단백질, Gc 단백질, NP 단백질을 이용한 SFTS 바이러스에 대한 백신 조성물을 제공하는 데 있다.An object of the present invention is to provide a vaccine composition against SFTS virus using Gn protein, Gc protein, and NP protein.
본 발명의 다른 목적이나 구체적인 목적은 이하에서 제시될 것이다.Other objects or specific objects of the present invention will be presented below.
본 발명자들은 아래의 실시예에서 확인되는 바와 같이, Gn 또는 Gc 단백질의 세포외 도메인(extracellular domain)이 사람 항체 Fc 부위에 융합된 재조합 단백질(Gn-Fc 및 Gc-Fc)과 NP 단백질(전장 서열의 단백질)을 개별로 제1형 인터페론 수용체 KO 생쥐에 면역하고 보호면역을 제공할 수 있는지를 비교검증 하였다. 그 결과 Gc-Fc 단백질은 면역한 생쥐는 모두 사망하였으나, 대조군(Fc만 면역한 그룹)에 비하여 생존 시간이 통계학적으로 유의하게 증가하였으며, Gn-Fc 단백질을 면역한 생쥐는 50%가 생존하였고, NP 단백질을 면역한 생쥐는 60%가 생존하여 각각 유의한 보호 면역 제공 효과가 있음을 확인하였다. 또한 Gn-Fc 및 Gc-Fc와 NP를 혼합하여 제1형 인터페론 수용체 KO 생쥐에 면역하여 보호면역이 상승하는지를 살펴 봤을 때, Gc-Fc와 NP의 혼합 면역의 경우 80%가 생존하였고, Gn-Fc와 NP의 혼합 면역의 경우는 70%가 생존하였으며, Gn-Fc와 Gc-Fc 그리고 NP의 혼합 면역의 경우는 60% 생존하여 전체적으로 혼합 면역의 경우가 개별 면역의 경우보다 생존율이 향상됨을 확인하였다.As confirmed in the Examples below, the present inventors have prepared recombinant proteins (Gn-Fc and Gc-Fc) in which the extracellular domain of Gn or Gc protein is fused to the Fc region of a human antibody and NP protein (full-length sequence). protein) was individually immunized to
본 발명은 이러한 실험 결과에 기초하여 제공되는 것으로, 본 발명의 백신 조성물은 Gc 단백질의 세포외 도메인, Gn 단백질의 세포외 도메인, 전장의 NP 단백질 또는 이들의 둘 이상의 혼합물을 활성성분으로 포함하는, SFTS 바이러스에 대한 백신 조성물에 관한 것이다.The present invention is provided based on these experimental results, and the vaccine composition of the present invention comprises, as an active ingredient, an extracellular domain of Gc protein, an extracellular domain of Gn protein, a full-length NP protein, or a mixture of two or more thereof, It relates to a vaccine composition against the SFTS virus.
본 발명에서, 특히 Gc 단백질의 세포외 도메인이나 Gn 단백질의 세포외 도메인은 생체 내 반감기를 향상시키기 위하여 사람 항체 Fc 부위에 융합된 형태일 수 있으며, Fc와 융합될 경우 각 융합되는 단백질이 서로 간에 3차원 구조 형성을 방해하지 않도록 2~15 아미노산을 가진 힌지(hinge) 서열이 게재될 수 있다. 또 이러한 단백질을 유전자 재조합 방식으로 숙주세포를 이용하여 생산하기 위해서는, 아래 실시예에서처럼 분리·정제를 용이하게 하기 위하여 신호 펩타이드(signal peptid) 서열이 N-말단에 위치할 수도 있다. 이러한 서열은 세포외로 해당 단백질이 분비될 때 제거되어 없어지기 때문에, 분리·정제된 단백질에서는 존재하지 않는다. In the present invention, in particular, the extracellular domain of the Gc protein or the extracellular domain of the Gn protein may be fused to a human antibody Fc region to improve in vivo half-life, and when fused to Fc, each fused protein interacts with each other. A hinge sequence with 2 to 15 amino acids can be inserted so as not to interfere with the formation of the three-dimensional structure. In addition, in order to produce these proteins using host cells by genetic recombination, a signal peptide sequence may be located at the N-terminus to facilitate separation and purification, as in the examples below. Since these sequences are removed when the protein is secreted to the outside of the cell, it does not exist in the isolated/purified protein.
본 명세서에서, "백신"은 숙주인 사람에게서 해당 병원체에 대한 면역 반응을 유도함으로써 해당 병원체의 감염 또는 재감염의 예방, 해당 병원체에 의한 증상의 중증도 감소 또는 증상의 제거, 또는 해당 병원체나 그 병원체 의한 질환의 실질적 또는 완전한 제거를 포함하는 의미이다. 따라서 본 발명의 백신 조성물은 해당 병원체의 감염 전에 예방적으로 사람에게 투여되거나 해당 병원체의 감염 후에 치료적으로 사람에게 투여될 수 있다. 여기서 상기 "면역 반응"은 체액성 면역 반응, 세포성 면역 반응 또는 이들을 모두 포함하는 의미이다. As used herein, "vaccine" refers to prevention of infection or re-infection of the pathogen by inducing an immune response against the pathogen in a human host, reduction of severity of symptoms caused by the pathogen, or elimination of symptoms caused by the pathogen or the pathogen. It is meant to include substantial or complete elimination of the disease. Therefore, the vaccine composition of the present invention can be administered to humans prophylactically before infection with the corresponding pathogen or therapeutically administered to humans after infection with the corresponding pathogen. Here, the "immune response" is meant to include a humoral immune response, a cellular immune response, or both.
또 본 명세서에서, "활성성분"은 단독으로 면역 반응을 유도하거나 또는 그 자체로는 면역 반응을 유도할 수 없는 담체와 함께 면역 반응을 유도할 수 있는 성분을 의미한다. 따라서 활성성분은 스스로가 반드시 면역원성(면역 반응을 유도할 수 있는 능력)을 가질 필요는 없다. 본 발명에서 상기 활성성분은 필수적이지는 않지만 정제된 것이 바람직하다. 여기서 "정제된"은 그 대상 물질이 존재하는 원래의 유기체(즉 본 발명에서는 형질전환된 미생물)의 세포 성분 또는 그 배양액 성분 등(오염물임)이 실질적으로 감소되었거나 제거된 상태를 의미한다. 오염물이 실질적으로 감소되었거나 제거된 상태는 순도가 50% 이상, 바람직하게는 90% 이상, 더 바람직하게는 99% 이상을 의미한다. 순도는 크로마토그래피, 겔 전기영동, 면역학적 분석 등 당업계에 공지된 방법을 통하여 평가될 수 있으며, 정제 방법도 후수하는 바와 같이 당업계에 공지된 방법을 이용할 수 있다. Also, in the present specification, "active ingredient" means a component capable of inducing an immune response alone or together with a carrier that cannot induce an immune response by itself. Therefore, the active ingredient itself does not necessarily have immunogenicity (the ability to induce an immune response). In the present invention, the active ingredient is preferably purified, although not essential. Here, “purified” refers to a state in which cell components of the original organism (ie, a transformed microorganism in the present invention) or its culture solution components (contaminants) in which the target substance exists are substantially reduced or removed. Substantially reduced or free of contaminants means a purity of 50% or more, preferably 90% or more, more preferably 99% or more. Purity can be evaluated through methods known in the art, such as chromatography, gel electrophoresis, and immunological analysis, and methods known in the art can be used as follows for purification methods.
본 발명의 백신 조성물은 임의의 적절한, 약학적으로 허용되는 제제로 제조될 수 있다. 예컨대 즉석 투여 용액 또는 현탁액 형태이거나, 투여 전 희석에 적절한 농축된 원액이거나, 또는 재구성 가능한 형태 예컨대 동결건조, 냉동-건조, 또는 냉동 제제 형태로 제조될 수 있다. The vaccine composition of the present invention can be prepared in any suitable, pharmaceutically acceptable formulation. For example, it may be in the form of an extemporaneous solution or suspension, a concentrated stock solution suitable for dilution prior to administration, or prepared in a reconstitutable form such as a lyophilized, freeze-dried, or frozen formulation.
본 발명의 백신 조성물은 약학적으로 허용되는 담체를 포함하여 제제화될 수 있다. 백신 조성물의 제제화를 위하여 사용될 수 있는 약학적으로 허용되는 담체는 대한민국 약전이나 제외국의 약전 특히 미국, 일본, 유럽의 약전에 열거·규정되어 있으며, 이들 약전을 참조할 수 있다. The vaccine composition of the present invention may be formulated by including a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that can be used for formulation of vaccine compositions are listed and regulated in the Korean Pharmacopoeia or other pharmacopeias, particularly in the US, Japan, and European pharmacopeias, and reference may be made to these pharmacopeias.
이러한 담체는 통상 희석제, 부형제, 안정화제, 방부제 등을 포함할 것이다. 적절한 희석제로서는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브유, 땅콩유와 같은 식물성유 등의 비수성 용매나 염수(바람직하게는 0.8%의 염수), 완충 매질을 포함한 물(바람직하게는 0.05M의 인산염 완충액) 등의 수성 용매 등을 들 수 있고, 적절한 부형제로서는 전분, 글루코스, 락토스, 수크로스, 젤라틴, 맥아, 쌀, 밀가루, 백악, 실리카 겔, 나트륨 스테아레이트, 글리세롤 모노스테아레이트, 활석, 나트륨 클로라이드, 무수 탈지유, 글리세롤, 프로필렌, 글리콜, 물, 에탄올 등을 들 수 있으며, 적절한 안정화제로서는 소르비톨, 만니톨, 전분, 수크로스, 덱스트란, 글루타메이트, 글루코스 등의 탄수화물이나 분유, 혈청 알부민, 카제인 등의 동물성, 식물성 또는 미생물성 단백질 등의 단백질을 들 수 있다. 적절한 방부제로서는 티메로살, 메르티올레이트, 젠타마이신, 네오마이신, 니스타틴, 암포테리신 B, 테트라사이클린, 페니실린, 스트렙토마이신, 폴리믹신 B 등을 들 수 있다.Such carriers will usually include diluents, excipients, stabilizers, preservatives, and the like. Suitable diluents include propylene glycol, polyethylene glycol, non-aqueous solvents such as vegetable oils such as olive oil and peanut oil, saline (preferably 0.8% saline), water containing a buffer medium (preferably 0.05M phosphate buffer), etc. suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, anhydrous skim milk , glycerol, propylene, glycol, water, ethanol, and the like, and suitable stabilizers include carbohydrates such as sorbitol, mannitol, starch, sucrose, dextran, glutamate, and glucose, or animal and vegetable substances such as milk powder, serum albumin, and casein. or proteins such as microbial proteins. Suitable preservatives include thimerosal, merthiolate, gentamicin, neomycin, nystatin, amphotericin B, tetracycline, penicillin, streptomycin, polymyxin B and the like.
본 발명의 백신 조성물은 항원 보조제(adjuvant)를 추가로 포함할 수 있다. 항원 보조제는 항원에 대한 면역 반응을 증강시키는 하나 이상의 물질로 이루어진 것일 수 있다. 보조제는 항원을 서서히 방출시키는 조직 저장소로서 및/또는 면역 반응을 비특이적으로 증강시키는 임파성 시스템 활성자로서 기능할 수 있다(Hood et al., Immunology, Second Ed., 1984, benjamin/Cummings: Menlo Park, California, p.384). 항원 보조제는 예컨대 완전 프로인트(Freund), 불완전 프로인트, 사포닌, 겔 성상의 알루미늄 보조제, 표면 활성 물질(예: 리소레시틴, 플루론 글리콜, 다중 음이온, 펩티드, 오일 또는 탄화수소 에멀젼 등), 식물성 오일(면실유, 땅콩유, 옥수수유 등), 비타민 E 아세테이트 등일 수 있다.The vaccine composition of the present invention may further include an antigen adjuvant. An antigenic adjuvant may consist of one or more substances that enhance an immune response to an antigen. Adjuvants can function as tissue depots that slowly release antigens and/or activators of the lymphatic system that non-specifically enhance immune responses (Hood et al., Immunology, Second Ed., 1984, benjamin/Cummings: Menlo Park , California, p.384). Antigenic adjuvants such as complete Freund's, incomplete Freund's, saponins, gelatinous aluminum adjuvants, surface active substances (eg lysolecithin, pluronic glycol, polyanions, peptides, oils or hydrocarbon emulsions, etc.), vegetable oils (cottonseed oil, peanut oil, corn oil, etc.), vitamin E acetate, and the like.
현재 인체에 적용 가능한 항원 보조제 중에서 가장 널리 사용되고 있는 것은 알루미늄 보조제이며, 이러한 알루미늄 보조제는 인산알루미늄(Aluminum phosphate), Potassium aluminum sulfate, 수산화 알루미늄(Aluminum hydroxide) 등 알루미늄 염(Aluminium salts)의 겔 성상으로 사용되고 있다. 이러한 알루미늄 보조제는 일반적으로 Th2-type의 면역반응을 이끌어내어 백신 효과를 증강시키는 것으로 알려져 있다(Sokolovska A et al., Vaccine. 2007 Jun 6;25(23):4575-85; O'Hagan DT AND Rappuoli R., Pharm Res. 2004 Sep;21(9):1519-30.) 본 발명의 실시예에서 사용한 Invivogen사의 Alhydrogel®은 수산화 알루미늄(Aluminium hydroxide)의 겔 형태 현탁액(colloidal)이다. 이러한 알루미늄 보조제는 그 제조 방법이 당업계에 공지되어 있어(R. Bomford. Immunological Adjuvants and Vaccines. NATO ASI Series 1989;179:35-41; Vogel FR AND Powell MF. Pharm Biotechnol. 1995;6:141-228.;Derek T. O'Hagan, Methods in Molecular Medicine. 2000; April 15; 42: 65-90) 직접 제조하여 사용하거나, 상업적으로 유통되는 제품을 구입하여 사용할 수도 있다. 상업적으로 유통되는 제품으로서는 아래의 실시예에서 사용된 Invivogen사의 Alhydrogel® 2% 제품을 비롯하여 Sigma사의 Aluminum hydroxide Gel 제품, BRENNTAG사의 Alhydrogel™ 제품 등을 들 수 있다.Currently, aluminum adjuvants are the most widely used among antigen adjuvants applicable to the human body, and these aluminum adjuvants are used in the gel form of aluminum salts such as aluminum phosphate, potassium aluminum sulfate, and aluminum hydroxide. there is. These aluminum adjuvants are generally known to elicit a Th2-type immune response to enhance vaccine efficacy (Sokolovska A et al., Vaccine. 2007 Jun 6;25(23):4575-85; O'Hagan DT AND Rappuoli R., Pharm Res. 2004 Sep;21(9):1519-30.) Invivogen's Alhydrogel® used in the examples of the present invention is a colloidal suspension of aluminum hydroxide. These aluminum adjuvants are well known in the art (R. Bomford. Immunological Adjuvants and Vaccines. NATO ASI Series 1989; 179: 35-41; Vogel FR AND Powell MF. Pharm Biotechnol. 1995; 6: 141- 228.; Derek T. O'Hagan, Methods in Molecular Medicine. 2000; April 15; 42: 65-90) It may be directly prepared and used, or a commercially distributed product may be purchased and used. Commercially distributed products include Invivogen's Alhydrogel® 2% product used in the examples below, Sigma's Aluminum hydroxide Gel product, BRENNTAG's Alhydrogel™ product, and the like.
본 발명의 백신 조성물은 임의적 단위 용량으로 제조될 수 있다. 단위 용량은 사람에 1회 이상 투여되기 위한 용도로 포장된 낱개의 제품에 포함된 활성성분과 약학적으로 허용되는 담체의 양을 말하는 것으로, 이러한 활성성분과 담체의 적절한 양은 본 발명의 백신 조성물이 1회 이상 접종될 때 백신으로서 기능할 수 있는 양으로 이러한 양은 당업자의 통상의 능력 범위 내에서 비임상적 및 임상적으로 결정될 수 있다. The vaccine composition of the present invention can be prepared in arbitrary unit doses. A unit dose refers to the amount of an active ingredient and a pharmaceutically acceptable carrier contained in an individual packaged product for one or more administration to humans, and the appropriate amount of such active ingredient and carrier is An amount capable of functioning as a vaccine when administered one or more times can be determined nonclinically and clinically within the ordinary skill of a person skilled in the art.
본 발명의 백신 조성물은 바람직하게는 비경구적으로 예컨대 직장, 경피, 정맥 내 주사, 동맥 내 주사, 근육 내 주사, 피 내 주사, 피하 주사, 복막 내 주사, 심실 내 주사 등을 통해 투여될 수 있다.The vaccine composition of the present invention can be preferably administered parenterally, such as rectally, transdermally, intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, intraperitoneally, intraventricularly, etc. .
본 발명의 백신 조성물은 조절 방출 시스템으로 투여될 수 있다. 예컨대 그러한 조절 방출 시스템으로서는 리포좀, 이식 삼투성 펌프, 경피 패치 등의 방식 등을 들 수 있다. 바람직하게는 리포좀 방식으로 활성성분을 전달하는 경우이다. 리포좀 방식에 의해 활성성분을 전달하는 것과 관련해서는 문헌[Langer, Science 249: 1527-1533 (1990)], 문헌[Treat at al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (des.), Liss, New York, pp. 353-365 (1989)] 등을 참조할 수 있다. 여타의 활성성분의 전달 방식과 관련해서는 문헌 [Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987)], 문헌[Buchwald et al., Surgery 88: 507 (1980)], 문헌[Saudek et al., N. Engl. J. Med. 321:574 (1989)], 문헌 [Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974)], 문헌[Controlled Drug Bioavailability. Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984)], 문헌[Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983)], 문헌[During et al., Ann. Neurol. 25:351 (1989)], 문헌[Howard et al., J. Neurosurg. 71:105 (1989)] 등을 참조할 수 있다. 이들 문헌은 본 명세서의 일부로서 간주된다.Vaccine compositions of the present invention can be administered as a controlled release system. Examples of such controlled-release systems include liposomes, implantable osmotic pumps, and transdermal patches. Preferably, it is the case of delivering an active ingredient in a liposomal manner. Regarding the delivery of active ingredients by liposome mode, see Langer, Science 249: 1527-1533 (1990), Treat at al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler. (des.), Liss, New York, pp. 353-365 (1989)] and the like. For other modes of delivery of active ingredients, see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987)], Buchwald et al., Surgery 88: 507 (1980), Saudek et al., N. Engl. J. Med. 321:574 (1989)], Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974), Controlled Drug Bioavailability. Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983)], During et al., Ann. Neurol. 25:351 (1989)], Howard et al., J. Neurosurg. 71:105 (1989)] and the like. These documents are considered part of this specification.
본 발명의 백신 조성물의 투여량은 의료인에 의해 나이, 체중, 성별, 증상, 합병증, 다른 질환의 이환 유무 등의 환자 특성을 고려하여 결정될 수 있다. The dosage of the vaccine composition of the present invention may be determined by a medical person in consideration of patient characteristics such as age, weight, sex, symptoms, complications, and presence or absence of other diseases.
또한 투여의 시간적 간격과 횟수는 사용되는 제형이나 활성성분의 혈중 반감기 등을 고려하여 결정될 수 있다. In addition, the time interval and frequency of administration may be determined in consideration of the dosage form used or the blood half-life of the active ingredient.
이처럼 투여량과 투여의 시간적 간격이나 횟수는 의료인의 판단에 따라 좌우되고 개인에 따라 결정되어야 하지만, 통상의 적절한 투여량은 1일 기준 개인 체중 1kg당 약 0.1 내지 10mg 범위 내에서 결정될 것이고 투여 간격은 3 내지 10일, 투여 횟수는 1 내지 5회 범위 내에서 결정될 것이다. As such, the dose and the time interval or frequency of administration depend on the judgment of the medical practitioner and should be determined individually, but the usual appropriate dose will be determined within the range of about 0.1 to 10 mg per 1 kg of individual body weight per day, and the administration interval is 3 to 10 days, the number of administrations will be determined within the range of 1 to 5 times.
본 발명의 백신 조성물에서 활성성분으로 사용되는 각 단백질은 이를 암호화하는 유전자를 이용하여 당업계에 공지된 DNA 재조합 기술로 제조할 수 있다. 이러한 방법은 (i) 상기 각 단백질을 암호화하는 유전자를 포함하는 발현벡터를 제조하고 (ii) 이 발현벡터를 숙주세포에 형질전환시키고 (iii) 형질전환된 숙주세포를 배양하고, 마지막으로 (iv) 그 배양물로부터 상기 각 단백질을 분리·정제하는 단계를 포함하여 구성된다. 상기 각 단백질을 암호화하는 유전자는 본 명세서에 개시되어 있으며, 이러한 유전자를 이용하여 DNA 재조합 기술로 해당 각 단백질을 생산하는 것, 구체적으로 프로모터나 터미네이터 등의 조절서열이나 신호 펩타이드 서열, 선별마커 등을 포함하는 발현벡터 구성이나 재조합 DNA 기술, 형질전환 방법, 배지의 구성, 형질전환 후 배양 방법 등에 대해서 당업계에 상당한 양의 문헌이 축적되어 있으며, 각 해당 사항에 대해서는 이들 문헌을 참조할 수 있다. 구체적으로 문헌(Nucl. Acid Res. 14:5399-5467, 1986), 문헌(Tet. Lett. 27:5575-5578, 1986), 문헌(Nucl. Acid Res. 4:2557, 1977), 문헌(Lett., 28:2449, 1978), 문헌(Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, (2001)), 문헌(F M Ausubel et al, Current Protocols in Molecular Biology, John Wiley amp; Sons, Inc. (1994)), 문헌(Marston, F (1987) DNA Cloning Techniques), 문헌(Cohen, S.N. et al., Proc. Natl. Acac. Sci. USA, 9:2110-2114(1973)), 문헌(Hanahan, D., J. Mol. Biol., 166:557-580(1983)), 문헌(Dower, W.J. et al., Nucleic. Acids Res., 16:6127-6145(1988)) (Capecchi, M.R., Cell, 22:479(1980)), 문헌(Graham, F.L. et al., Virology, 52:456(1973)), 문헌(Neumann, E. et al., EMBO J., 1:841(1982)), 문헌(Wong, T.K. et al., Gene, 10:87(1980)), 문헌(Gopal, Mol. Cell Biol., 5:1188-1190(1985)), 문헌(Yang et al., Proc. Natl. Acad. Sci., 87:9568-9572(1990)) 문헌(Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory (1982)) 문헌(Hitzeman et al., J. Biol. Chem., 255, 12073-12080 (1980)), 문헌(Luchansky et al Mol. Microbiol. 2, 637-646 (1988)), 문헌(Sambrook 등, Molecular Cloning A Laboratory Mannual, Cold Spring Harbor Laboratory Press, US(1989)), 문헌(Ausubel 등, Current Protocols in Molecular Biology, Jon Willey & Sons, US(1993)), 문헌(Sambrook, J. & Russel, D. 저, Molecular Cloning, A LABORATORY MANUAL, Cold Spring Harbor Laboratory Press, 2001년 1월 15일 발행의 제1권 및 제2권) 등을 참조할 수 있다. Each protein used as an active ingredient in the vaccine composition of the present invention can be prepared by DNA recombination technology known in the art using a gene encoding the protein. This method (i) prepares an expression vector containing the gene encoding each protein, (ii) transforms the expression vector into a host cell, (iii) cultures the transformed host cell, and finally (iv) ) isolating and purifying each of the above proteins from the culture. Genes encoding each of the above proteins are disclosed herein, and production of each corresponding protein by DNA recombination technology using these genes, specifically, control sequences such as promoters or terminators, signal peptide sequences, selection markers, etc. A considerable amount of literature has been accumulated in the art regarding the construction of expression vectors, recombinant DNA technology, transformation methods, culture methods after transformation, and the like, and these documents can be referred to for each relevant matter. Specifically, literature (Nucl. Acid Res. 14:5399-5467, 1986), literature (Tet. Lett. 27:5575-5578, 1986), literature (Nucl. Acid Res. 4:2557, 1977), literature (Lett. ., 28:2449, 1978), Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, (2001), F M Ausubel et al, Current Protocols in Molecular Biology, John Wiley amp Sons, Inc. (1994), Marston, F (1987) DNA Cloning Techniques, Cohen, S.N. et al., Proc. Natl. Acac. Sci. USA, 9:2110-2114 (1973). ), Hanahan, D., J. Mol. Biol., 166:557-580 (1983), Dower, W.J. et al., Nucleic. Acids Res., 16:6127-6145 (1988). (Capecchi, M.R., Cell, 22:479 (1980)), (Graham, F.L. et al., Virology, 52:456 (1973)), (Neumann, E. et al., EMBO J., 1: 841 (1982)), Wong, T.K. et al., Gene, 10:87 (1980), Gopal, Mol. Cell Biol., 5:1188-1190 (1985), Yang et al. ., Proc. Natl. Acad. Sci., 87:9568-9572 (1990) (Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory (1982)) (Hitzeman et al., J Biol. Chem., 255, 12073-12080 (1980)), Luchansky et al Mol. Microbiol. 2, 637-646 (1988)), Sambrook et al., Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory Press, US (1989), Ausubel et al., Current Protocols in Molecular Biology, Jon Willey & Sons, US (1993)), by Sambrook, J. & Russel, D., Molecular Cloning, A LABORATORY MANUAL, Cold Spring Harbor Laboratory Press,
본 발명은 전술한 바와 같이, Gc 단백질의 세포외 도메인, Gn 단백질의 세포외 도메인, 전장의 NP 단백질 또는 이들의 혼합물을 활성성분으로 하는, SFTS 바이러스에 대한 백신 조성물을 제공할 수 있다. As described above, the present invention can provide a vaccine composition against the SFTS virus, comprising the extracellular domain of the Gc protein, the extracellular domain of the Gn protein, the full-length NP protein, or a mixture thereof as an active ingredient.
도 1은 본 발명의 백신 조성물의 활성성분인 Gc 단백질, Gn 단백질 또는 NP 단백질의 구조와 분자량을 나타낸 도면이다.
도 2는 본 발명의 백신 조성물의 활성성분인 Gc 단백질, Gn 단백질 또는 NP 단백질의 SDS-PAGE 결과이다.
도 3은 Gn 및 Gc 항원 면역에 의한 특이 항체 유도 및 면역 혈청을 이용한 바이러스 중화능 검사 결과이다(a. Gn 및 Gn 단백질에 대한 항체 역가. b and c. SFTS 바이러스에 대한 중화능 분석 시험. FRNT: focus reduction neutralization titer)
도 4는 Gc 단백질, Gn 단백질 또는 NP 단백질을 제1형 인터페론 수용체 KO 생쥐에 면역하고 생존율과 체중 변화를 측정한 결과이다.
도 5는 Gc 단백질, Gn 단백질 및/또는 NP 단백질의 혼합물을 제1형 인터페론 수용체 KO 생쥐에 면역하고 생존율과 체중 변화를 측정한 결과이다.1 is a diagram showing the structure and molecular weight of Gc protein, Gn protein or NP protein, which are active ingredients of the vaccine composition of the present invention.
2 is an SDS-PAGE result of Gc protein, Gn protein or NP protein, which are active ingredients of the vaccine composition of the present invention.
Figure 3 shows the results of specific antibody induction by Gn and Gc antigen immunization and virus neutralization ability test using immune serum (a. Antibody titer against Gn and Gn protein. b and c. Neutralization ability assay test against SFTS virus. FRNT : focus reduction neutralization titer)
4 shows the results of survival rate and body weight change after immunizing
5 shows the results of survival rate and body weight change after immunizing
이하 본 발명을 실시예를 참조하여 설명한다. 그러나 본 발명의 범위가 이러한 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described with reference to examples. However, the scope of the present invention is not limited to these examples.
<실시예 1> 백신 항원으로 사용될 바이러스 단백질의 생산<Example 1> Production of viral proteins to be used as vaccine antigens
<실시예 1-1> 백신 항원으로 사용될 바이러스 단백질의 아미노산 서열<Example 1-1> Amino acid sequence of viral protein to be used as vaccine antigen
GenBank 상의 아미노산 정보를 이용하여 백신 항원으로 사용될 바이러스 Gn 단백질, Gc 단백질 및 NP 단백질의 생산하였다. GenBank 상의 아미노산 정보는 GenBank ID: ATW63054.1(Gn 단백질), GenBank ID: AOO85591.1(Gc 단백질), GenBank ID: AJO16084.1(NP 단백질)이다.Using the amino acid information on GenBank, viral Gn protein, Gc protein and NP protein to be used as vaccine antigens were produced. Amino acid information on GenBank is GenBank ID: ATW63054.1 (Gn protein), GenBank ID: AOO85591.1 (Gc protein), GenBank ID: AJO16084.1 (NP protein).
Gn과 Gc 단백질은 signal peptide와 transmembrane domain 및 cytoplasmic domain을 제외한 extracellular domain 만(각각 서열번호 1 및 2)을 사용하였으며, NP 단백질은 전장 서열(서열번호 3)을 사용하였다.For the Gn and Gc proteins, only signal peptide, transmembrane domain, and extracellular domain except for the cytoplasmic domain (SEQ ID NOs: 1 and 2, respectively) were used, and the full-length sequence (SEQ ID NO: 3) was used for the NP protein.
<실시예 1-2> 바이러스 단백질 유전자 클로닝 및 발현<Example 1-2> Virus protein gene cloning and expression
Gn 및 Gc 단백질(extracellular domain)을 암호화하는 유전자(각각 서열번호 4 및 5)를 합성한 후 도 1과 같이 사람 Ig kappa light chain의 signal peptide 유전자(서열번호 6)가 N-terminal에 융합되고 human IgG1 CH2-CH3 부위 Fc domain 유전자(서열번호 7)가 힌지 서열(hinge region)(서열번호 8)을 매개로 C-terminal에 융합된 재조합 유전자를 pCEP4 mammalian expression vector에 클로닝 하였다. N-terminal과 C-terminal 각각에 6 His(정제를 위하여 사용함)가 연결된 NP 단백질을 암호화하는 유전자(서열번호 9)는 pET28a vector에 클로닝 하였다. 클로닝된 유전자는 각각 HEK293T 세포(Gn, Gc)와 E.coli BL21 (NP)에 도입하여 단백질 발현을 유도하였으며, Protein A/G column과 Ni-NTA column을 이용하여 각각 정제하였다. 정제된 단백질의 크기와 순도는 SDS-PAGE를 통해 확인하였다(도 2).After synthesizing genes encoding Gn and Gc proteins (extracellular domain) (SEQ ID NOs: 4 and 5, respectively), the signal peptide gene (SEQ ID NO: 6) of human Ig kappa light chain is fused to the N-terminal as shown in FIG. 1, and human The recombinant gene in which the IgG1 CH2-CH3 Fc domain gene (SEQ ID NO: 7) was fused to the C-terminal via the hinge region (SEQ ID NO: 8) was cloned into pCEP4 mammalian expression vector. The gene (SEQ ID NO: 9) encoding the NP protein with 6 His (used for purification) linked to each of the N-terminal and C-terminal was cloned into a pET28a vector. The cloned gene was introduced into HEK293T cells (Gn, Gc) and E.coli BL21 (NP) to induce protein expression, and purified using Protein A/G column and Ni-NTA column, respectively. The size and purity of the purified protein was confirmed by SDS-PAGE (FIG. 2).
<실시예 2> SFTS 바이러스 단백질의 면역과 항체 분석<Example 2> Immunity and antibody analysis of SFTS virus proteins
Gn-Fc(서열번호 10, 서열번호 10에서 N-terminal의 DVAQAA 아미노산 서열은 클로닝을 위하여 삽입된 서열임), Gc-Fc(서열번호 11, 서열번호 10에서 N-terminal의 DVAQAA 아미노산 서열은 클로닝을 위하여 삽입된 서열임), NP(서열번호 12), 사람 Fc를 각각 제1형 인터페론 수용체 KO 생쥐(n=4)에 2주 간격으로 3회 면역하고 (20ug/mouse +Alum, Gn-Fc, Gc-Fc, Fc; 10ug/mouse + Alum, NP), 3차 면역 2주 후 혈액을 채취하여 Gn, Gc, 및 NP에 대한 항체 역가를 ELISA 방법으로 측정하였다(도 3의 a). 각 항원에 대하여 높은 수준의 항체들이 생성됨을 확인 하였으며(anti-Gn 또는 anti-Gc IgG 평균 titer = 1:4,096, anti-NP IgG 평균 titer = 1:24,576; n = 4/group), 특히 NP 항원에 대한 항체 역가가 높게 유도되는 것이 관찰되었다. 바이러스 당단백질들(Gn과 Gc)에 대해 생성된 항체들의 바이러스 중화능을 확인하기 위하여 SFTS 바이러스를 면역혈청과 반응시키고, Vero 세포에 감염시켜 focus reduction assay를 실시였다 (도 3의 b 및 c). 거의 유사한 수준의 항체가 생성되었음에도 불구하고, Gn-Fc를 면역하여 얻은 혈청이 Gc-Fc를 면역하여 얻은 혈청보다 좀 더 높은 중화 항체가를 형성하였으며, 두 가지 면역 혈청 모두 Fc만을 면역하여 얻은 혈청보다 유의하게 높은 수준의 바이러스 중화능을 보유 하고 있음이 확인되었다 (중화항체 역가: Gn-Fc: 929 ± 1134, Gc-Fc: 209 ± 140, Fc: 42 ± 29; n = 4/group, mean titer ± S.D.). Gn-Fc (SEQ ID NO: 10, N-terminal DVAQAA amino acid sequence in SEQ ID NO: 10 is inserted for cloning), Gc-Fc (SEQ ID NO: 11, N-terminal DVAQAA amino acid sequence in SEQ ID NO: 10 is cloned) ), NP (SEQ ID NO: 12), and human Fc were immunized with
<실시예 3> SFTS 바이러스 단백질 면역에 의한 보호 면역 효과<Example 3> Protective immune effect by SFTS virus protein immunization
Gn-Fc, Gc-Fc, NP, Fc를 각각 제1형 인터페론 수용체 KO 생쥐(n=4~6)에 2주 간격으로 3회 면역하고 (20ug/mouse +Alum, Gn-Fc, Gc-Fc, Fc; 10ug/mouse + Alum, NP), 3차 면역 2주 후 103 foci-forming unit (FFU)의 SFTS 바이러스를 피하로 감염시켰다. 그리고 매일 몸무게 변화와 사망률을 관찰하였다(도 4).
PBS를 면역한 생쥐들(대조군)은 몸무게가 서서히 줄고, 감염 6일째까지 모두 사망하였다. Fc를 면역한 생쥐들(대조군)은 감염 이틀째부터 몸무게가 서서히 줄고, 감염 5일째까지 모두 사망하였다. Gc-Fc를 면역한 생쥐들은 감염 4일째부터 몸무게가 줄기 시작하였고, 감염 8일째 모두 사망하였다. Gn-Fc를 면역한 생쥐들은 감염 3일째부터 몸무게가 줄기 시작하였고, 감염 8일째까지 절반이 사망하였으나 나머지 생쥐들은 이후 몸무게가 회복되고 생존하였다. NP를 면역한 생쥐들은 감염 3일째부터 몸무게가 줄기 시작하였으며, 8일째까지 40%가 사망하였으며, 나머지 60% 생쥐들은 이후 서서히 몸무게를 회복하고 생존하였다. 통계학적 분석을 하였을 때 (Log-rank (Mantel-Cox) Test), 백신에 의한 생존 연장 효과 (Gc-Fc 군: p = 0.0046), 또는 사망률 감소 효과 (Gn-Fc 군: p = 0.0054, NP 군: p = 0.0023)는 대조군에 비하여 통계학적으로 유의한 향상을 보이는 것이 확인되었다.Mice immunized with PBS (control group) gradually lost weight and all died by the 6th day of infection. Mice immunized with Fc (control group) gradually lost weight from the second day of infection and all died by the fifth day of infection. Mice immunized with Gc-Fc began to lose weight on the 4th day after infection, and all died on the 8th day after infection. Mice immunized with Gn-Fc began to lose weight on the 3rd day of infection, and half of them died by the 8th day of infection, but the rest of the mice recovered their body weight and survived. Mice immunized with NP began to lose weight from the third day of infection, and 40% died by the eighth day, and the remaining 60% mice gradually recovered their body weight and survived. When statistical analysis was performed (Log-rank (Mantel-Cox) Test), the effect of vaccine prolonging survival (Gc-Fc group: p = 0.0046) or reducing mortality (Gn-Fc group: p = 0.0054, NP Group: p = 0.0023) was confirmed to show a statistically significant improvement compared to the control group.
<실시예 4> SFTS 바이러스 단백질 혼합 면역에 의한 보호 면역 효과<Example 4> Protective immune effect by SFTS virus protein mixed immunization
Gn-Fc와 NP의 혼합물(Gn+NP, 혼합비: 10ug + 10ug), Gc-Fc와 NP의 혼합물(Gc+NP, 혼합비: 10ug + 10ug), Gn-Fc와 Gc-Fc 그리고 NP의 혼합물(Gn+Gc+NP, 혼합비: 10ug + 10ug + 10ug), PBS(Control)를 각각 제1형 인터페론 수용체 KO 생쥐(n=7)에 2주 간격으로 3회 면역하고(20 or 30ug/mouse, +Alum), 3차 면역 2주 후 103 foci-forming unit (FFU)의 SFTS 바이러스를 피하로 감염시켰다. 그리고 매일 몸무게 변화와 사망률을 관찰하였다(도 5).A mixture of Gn-Fc and NP (Gn + NP, mixing ratio: 10ug + 10ug), a mixture of Gc-Fc and NP (Gc + NP, mixing ratio: 10ug + 10ug), a mixture of Gn-Fc and Gc-Fc and NP ( Gn+Gc+NP, mixing ratio: 10ug + 10ug + 10ug) and PBS (Control) were immunized with
PBS를 면역한 생쥐들(대조군)은 몸무게가 서서히 줄고, 감염 6일째까지 모두 사망하였다. Gn+NP를 면역한 생쥐들은 감염 4일째부터 몸무게가 줄기 시작하였고, 감염 5일째 14.3%가 사망하고 감염 6일째까지 28.6% 사망하였으나 나머지 생쥐들은 이후 몸무게가 회복하고 생존하였다. Gc+NP를 면역한 생쥐들은 감염 5일째부터 몸무게가 줄기 시작하였고, 감염 6일째 14.3%가 사망하였으나 나머지 생쥐들은 이후 몸무게가 회복하고 생존하였다. Gn+Gc+NP를 면역한 생쥐들은 4일째부터 몸무게가 줄기 시작하였고, 감염 7일째 42.9%가 사망하였으나 나머지 생쥐들은 이후 몸무게가 회복하고 생존하였다. Mice immunized with PBS (control group) gradually lost weight and all died by the 6th day of infection. Mice immunized with Gn+NP began to lose weight on the 4th day of infection, 14.3% died on the 5th day of infection and 28.6% died by the 6th day of infection, but the rest of the mice recovered their body weight and survived. Mice immunized with Gc+NP began to lose weight on the 5th day of infection, and 14.3% died on the 6th day of infection, but the rest of the mice recovered their body weight and survived. Mice immunized with Gn+Gc+NP began to lose weight on the 4th day, and 42.9% died on the 7th day of infection, but the rest of the mice recovered their weight and survived.
통계학적 분석을 하였을 때 (Log-rank (Mantel-Cox) Test), 백신에 의한 생존 연장 효과 (Gc-Fc 군: p = 0.0046), 또는 사망률 감소 효과 (Gn-Fc 군: p = 0.0054, NP 군: p = 0.0023)는 대조군에 비하여 통계학적으로 유의한 향상을 보이는 것이 확인되었다.When statistical analysis was performed (Log-rank (Mantel-Cox) Test), the effect of vaccine prolonging survival (Gc-Fc group: p = 0.0046) or reducing mortality (Gn-Fc group: p = 0.0054, NP Group: p = 0.0023) was confirmed to show a statistically significant improvement compared to the control group.
<110> SNU R&DB Foundation <120> Vaccine Composition for SFTS virus <130> PP19-000-SNU-CHO <160> 12 <170> KoPatentIn 3.0 <210> 1 <211> 438 <212> PRT <213> Unknown <220> <223> Extracellular domain of Gn protein of SFTS virus <400> 1 Asp Ser Gly Pro Ile Ile Cys Ala Gly Pro Ile His Ser Asn Lys Ser 1 5 10 15 Ala Asp Ile Pro His Leu Leu Gly Tyr Ser Glu Lys Ile Cys Gln Ile 20 25 30 Asp Arg Leu Ile His Val Ser Ser Trp Leu Arg Asn His Ser Gln Phe 35 40 45 Gln Gly Tyr Val Gly Gln Arg Gly Gly Arg Ser Gln Val Ser Tyr Tyr 50 55 60 Pro Ala Glu Asn Ser Tyr Ser Arg Trp Ser Gly Leu Leu Ser Pro Cys 65 70 75 80 Asp Ala Asp Trp Leu Gly Met Leu Val Val Lys Lys Ala Lys Gly Ser 85 90 95 Asp Met Ile Val Pro Gly Pro Ser Tyr Lys Gly Lys Val Phe Phe Glu 100 105 110 Arg Pro Thr Phe Asp Gly Tyr Val Gly Trp Gly Cys Gly Ser Gly Lys 115 120 125 Ser Arg Thr Glu Ser Gly Glu Leu Cys Ser Ser Asp Ser Gly Thr Ser 130 135 140 Ser Gly Leu Leu Pro Ser Asp Arg Val Leu Trp Ile Gly Asp Val Ala 145 150 155 160 Cys Gln Pro Met Thr Pro Ile Pro Glu Glu Thr Phe Leu Glu Leu Lys 165 170 175 Ser Phe Ser Gln Ser Glu Phe Pro Asp Ile Cys Lys Ile Asp Gly Ile 180 185 190 Val Phe Asn Gln Cys Glu Gly Glu Ser Leu Pro Gln Pro Phe Asp Val 195 200 205 Ala Trp Met Asp Val Gly His Ser His Lys Ile Ile Met Arg Glu His 210 215 220 Lys Thr Lys Trp Val Gln Glu Ser Ser Ser Lys Asp Phe Val Cys Tyr 225 230 235 240 Lys Glu Gly Thr Gly Pro Cys Ser Glu Ser Glu Glu Lys Thr Cys Lys 245 250 255 Thr Ser Gly Ser Cys Arg Gly Asp Met Gln Phe Cys Lys Val Ala Gly 260 265 270 Cys Glu His Gly Glu Glu Ala Ser Glu Ala Lys Cys Arg Cys Ser Leu 275 280 285 Val His Lys Pro Gly Glu Val Val Val Ser Tyr Gly Gly Met Arg Val 290 295 300 Arg Pro Lys Cys Tyr Gly Phe Ser Arg Met Met Ala Thr Leu Glu Val 305 310 315 320 Asn Gln Pro Glu Gln Arg Ile Gly Gln Cys Thr Gly Cys His Leu Glu 325 330 335 Cys Ile Asn Gly Gly Val Arg Leu Ile Thr Leu Thr Ser Glu Leu Lys 340 345 350 Ser Ala Thr Val Cys Ala Ser His Phe Cys Ser Ser Ala Thr Ser Gly 355 360 365 Lys Lys Ser Thr Glu Ile Gln Phe His Ser Gly Ser Leu Val Gly Lys 370 375 380 Thr Ala Ile His Val Lys Gly Ala Leu Val Asp Gly Thr Glu Phe Thr 385 390 395 400 Phe Glu Gly Ser Cys Met Phe Pro Asp Gly Cys Asp Ala Val Asp Cys 405 410 415 Thr Phe Cys Arg Glu Phe Leu Lys Asn Pro Gln Cys Tyr Pro Ala Lys 420 425 430 Lys Gly Gln Ala Gly Gln 435 <210> 2 <211> 473 <212> PRT <213> Unknown <220> <223> Extracellular domain of Gc protein of SFTS virus <400> 2 Cys Asp Glu Met Val His Ala Asp Ser Lys Leu Val Ser Cys Arg Gln 1 5 10 15 Gly Ser Gly Asn Met Lys Glu Cys Val Thr Thr Gly Arg Ala Leu Leu 20 25 30 Pro Ala Val Asn Pro Gly Gln Glu Ala Cys Leu His Phe Thr Ala Pro 35 40 45 Gly Ser Pro Asp Ser Lys Cys Leu Lys Ile Lys Val Lys Arg Ile Asn 50 55 60 Leu Lys Cys Lys Lys Ser Ser Ser Tyr Phe Val Pro Asp Ala Arg Ser 65 70 75 80 Arg Cys Thr Ser Val Arg Arg Cys Arg Trp Ala Gly Asp Cys Gln Ser 85 90 95 Gly Cys Pro Pro His Phe Thr Ser Asn Ser Phe Ser Asp Asp Trp Ala 100 105 110 Gly Lys Met Asp Arg Ala Gly Leu Gly Phe Ser Gly Cys Ser Asp Gly 115 120 125 Cys Gly Gly Ala Ala Cys Gly Cys Phe Asn Ala Ala Pro Ser Cys Ile 130 135 140 Phe Trp Arg Lys Trp Val Glu Asn Pro His Gly Ile Ile Trp Lys Val 145 150 155 160 Ser Pro Cys Ala Ala Trp Val Pro Ser Ala Val Ile Glu Leu Thr Met 165 170 175 Pro Ser Gly Glu Val Arg Thr Phe His Pro Met Ser Gly Ile Pro Thr 180 185 190 Gln Val Phe Lys Gly Val Ser Val Thr Tyr Leu Gly Ser Asp Met Glu 195 200 205 Val Ser Gly Leu Thr Asp Leu Cys Glu Ile Glu Glu Leu Lys Ser Lys 210 215 220 Lys Leu Ala Leu Ala Pro Cys Asn Gln Ala Gly Met Gly Val Val Gly 225 230 235 240 Lys Val Gly Glu Ile Gln Cys Ser Ser Glu Glu Ser Ala Arg Thr Ile 245 250 255 Lys Lys Asp Gly Cys Ile Trp Asn Ala Asp Leu Val Gly Ile Glu Leu 260 265 270 Arg Val Asp Asp Ala Val Cys Tyr Ser Lys Ile Thr Ser Val Glu Ala 275 280 285 Val Ala Asn Tyr Ser Ala Ile Pro Thr Thr Ile Gly Gly Leu Arg Phe 290 295 300 Glu Arg Ser His Asp Ser Gln Gly Lys Ile Ser Gly Ser Pro Leu Asp 305 310 315 320 Ile Thr Ala Ile Arg Gly Ser Phe Ser Val Asn Tyr Arg Gly Leu Arg 325 330 335 Leu Ser Leu Ser Glu Ile Thr Ala Thr Cys Thr Gly Glu Val Thr Asn 340 345 350 Val Ser Gly Cys Tyr Ser Cys Met Thr Gly Ala Lys Val Ser Ile Lys 355 360 365 Leu His Ser Ser Lys Asn Ser Thr Ala His Val Arg Cys Lys Gly Asp 370 375 380 Glu Thr Ala Phe Ser Val Leu Glu Gly Val His Ser Tyr Thr Val Ser 385 390 395 400 Leu Ser Phe Asp His Ala Val Val Asp Glu Gln Cys Gln Leu Asn Cys 405 410 415 Gly Gly His Glu Ser Gln Val Thr Leu Lys Gly Asn Leu Ile Phe Leu 420 425 430 Asp Val Pro Lys Phe Val Asp Gly Ser Tyr Met Gln Thr Tyr His Ser 435 440 445 Thr Val Pro Thr Gly Ala Asn Ile Pro Ser Pro Thr Asp Trp Leu Asn 450 455 460 Ala Leu Phe Gly Asn Gly Leu Ser Arg 465 470 <210> 3 <211> 245 <212> PRT <213> Unknown <220> <223> NP protein of SFTS virus <400> 3 Met Ser Glu Trp Ser Arg Ile Ala Val Glu Phe Gly Glu Gln Gln Leu 1 5 10 15 Asn Leu Ser Glu Leu Glu Asp Phe Ala Arg Glu Leu Ala Tyr Glu Gly 20 25 30 Leu Asp Pro Ala Leu Ile Ile Lys Lys Leu Lys Glu Thr Gly Gly Asp 35 40 45 Asp Trp Val Lys Asp Thr Lys Phe Ile Ile Val Phe Ala Leu Thr Arg 50 55 60 Gly Asn Lys Ile Val Lys Ala Ser Gly Lys Met Ser Asn Ser Gly Ser 65 70 75 80 Lys Arg Leu Met Ala Leu Gln Glu Lys Tyr Gly Leu Val Glu Arg Ala 85 90 95 Glu Thr Arg Leu Ser Ile Thr Pro Val Arg Val Ala Gln Ser Leu Pro 100 105 110 Thr Trp Thr Cys Ala Ala Ala Ala Ala Leu Lys Glu Tyr Leu Pro Val 115 120 125 Gly Pro Ala Val Met Asn Leu Lys Val Glu Asn Tyr Pro Pro Glu Met 130 135 140 Met Cys Met Ala Phe Gly Ser Leu Ile Pro Thr Ala Gly Val Ser Glu 145 150 155 160 Ala Thr Thr Lys Thr Leu Met Glu Ala Tyr Ser Leu Trp Gln Asp Ala 165 170 175 Phe Thr Lys Thr Ile Asn Val Lys Met Arg Gly Ala Ser Lys Thr Glu 180 185 190 Val Tyr Asn Ser Phe Arg Asp Pro Leu His Ala Ala Val Asn Ser Val 195 200 205 Phe Phe Pro Asn Asp Val Arg Val Lys Trp Leu Lys Ala Lys Gly Ile 210 215 220 Leu Gly Pro Asp Gly Val Pro Ser Arg Ala Ala Glu Val Ala Ala Ala 225 230 235 240 Ala Tyr Arg Asn Leu 245 <210> 4 <211> 1299 <212> DNA <213> Unknown <220> <223> gene encoding excellular domain of Gn protein of SFTS virus <400> 4 gactctggac ctattatctg tgctggacct attcattcaa acaaatctgc tgacatccct 60 catctgctgg gctactccga aaaaatctgc cagattgatc gactgatcca cgtgagctcc 120 tggctgcgga accatagcca gttccaggga tacgtcggac agaggggcgg gcgctctcag 180 gtgagttact atccagccga gaacagctac agccggtggt ccggactgct gtctccatgt 240 gacgcagatt ggctgggaat gctggtggtc aagaaagcta agggctcaga tatgattgtc 300 cccggcccta gctacaaggg gaaagtgttc tttgaacgcc ccaccttcga cggctatgtg 360 ggctgggggt gcggatcagg caaaagccga acagagtccg gagaactgtg cagcagcgac 420 tctggaactt caagcggcct gctgcctagc gatagggtcc tgtggattgg cgacgtggcc 480 tgccagccaa tgaccccaat ccccgaggaa acatttctgg agctgaagag tttctcacag 540 agcgaatttc cagacatctg caaaattgac ggcatcgtgt tcaaccagtg tgagggggaa 600 agcctgcctc agccatttga tgtcgcttgg atggacgtgg gccactccca taagatcatt 660 atgcgcgagc acaagactaa atgggtccag gaatcctcta gtaaggattt cgtgtgctac 720 aaagagggga ccggaccctg ttccgaatct gaggaaaaga cttgcaaaac cagtgggtca 780 tgtcggggag acatgcagtt ttgcaaggtg gctggctgtg agcacgggga ggaagcctct 840 gaagctaaat gcagatgtag tctggtccat aaacccggcg aggtggtcgt gagttacgga 900 ggcatgcggg tgagacctaa atgctatggg ttcagcagaa tgatggcaac cctggaggtg 960 aaccagcctg aacagaggat cggacagtgc acaggctgtc acctggagtg tattaatggg 1020 ggagtccgac tgatcaccct gacaagtgaa ctgaagtcag caacagtgtg cgcctctcat 1080 ttctgttcaa gcgccactag cggcaagaaa tccaccgaga ttcagtttca cagcgggtcc 1140 ctggtgggaa agactgctat ccatgtcaaa ggagcactgg tggatggcac agagttcact 1200 tttgaagggt cctgcatgtt tccagacgga tgtgatgcag tggactgcac attctgtcgc 1260 gagtttctga agaatcccca gtgctatcct gccaagaaa 1299 <210> 5 <211> 1419 <212> DNA <213> Unknown <220> <223> gene encoding excellular domain of Gc protein of SFTS virus <400> 5 tgcgatgaaa tggtccacgc cgatagcaaa ctggtcagct gtaggcaggg aagcgggaac 60 atgaaggaat gcgtcacaac cggaagagct ctgctgccag cagtgaaccc tggacaggag 120 gcctgcctgc acttcacagc tcctggaagt ccagactcaa aatgcctgaa gatcaaagtg 180 aagcggatta atctgaagtg taagaaaagc tcctcttact ttgtgcccga cgcaaggtca 240 cgctgcacta gcgtccggag atgtagatgg gcaggcgatt gccagagcgg atgtccacct 300 catttcacct ctaacagttt ttcagacgat tgggcaggca agatggacag ggcaggactg 360 gggttcagcg gatgctccga tggatgtgga ggagcagctt gcggatgttt caacgcagcc 420 ccctcctgca tcttttggcg caaatgggtg gagaatcctc acggcatcat ttggaaggtc 480 tccccttgtg ctgcatgggt gccatctgcc gtcatcgagc tgacaatgcc cagcggcgaa 540 gtgagaactt tccatccaat gtccgggatt cccacccagg tctttaaggg agtgtctgtc 600 acatatctgg gcagcgacat ggaggtgtcc gggctgactg atctgtgcga aatcgaggaa 660 ctgaaatcca agaaactggc cctggctcct tgtaatcagg caggaatggg agtggtcggc 720 aaggtcgggg agattcagtg cagttcagag gaaagcgcac gcaccatcaa gaaagacggg 780 tgtatttgga acgccgatct ggtgggaatc gagctgcgag tggacgatgc tgtctgctac 840 tccaaaatta catctgtgga agcagtcgcc aattattccg ctatccctac cacaattggc 900 ggcctgcgat tcgaacggtc tcacgacagt caggggaaga tcagcggcag ccccctggac 960 atcaccgcca ttcgaggatc ttttagtgtg aactacagag gcctgaggct gtcactgagc 1020 gagatcactg ctacctgcac aggagaagtg actaatgtca gtggctgcta ttcatgtatg 1080 accggggcaa aagtgagtat taagctgcac agctccaaaa actcaacagc tcatgtgcgc 1140 tgtaagggag acgagactgc attctctgtg ctggaaggcg tccacagtta cacagtgtcc 1200 ctgtcttttg accatgccgt ggtcgatgag cagtgccagc tgaactgtgg gggacacgaa 1260 agccaagtga ctctgaaagg caatctgatc ttcctggacg tgccaaagtt tgtcgatggg 1320 tcatacatgc agacctatca tagcactgtg cccaccggcg ccaatattcc atctcccaca 1380 gattggctga acgctctgtt tgggaatgga ctgagtcgg 1419 <210> 6 <211> 60 <212> DNA <213> Unknown <220> <223> gene encoding signal peptide <400> 6 atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccactggt 60 60 <210> 7 <211> 654 <212> DNA <213> Unknown <220> <223> gene encoding human Fc <400> 7 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ccccgggtaa atga 654 <210> 8 <211> 60 <212> DNA <213> Unknown <220> <223> gene encoding hinge region <400> 8 ggccaggccg gccaggagcc caaatctagc gacaaaactc acacaagccc accgagccca 60 60 <210> 9 <211> 738 <212> DNA <213> Unknown <220> <223> gene encoding NP protein of SFTS virus <400> 9 atgtcggagt ggtccaggat tgcagtggag tttggtgagc agcagctcaa tttgtctgag 60 cttgaggatt tcgcgagaga actggcctat gaaggccttg accctgcttt gatcatcaag 120 aagctgaagg agacaggtgg agatgattgg gtgaaggata caaagttcat cattgtcttt 180 gccctgactc gaggcaacaa gatcgtcaag gcatcaggga aaatgtcaaa ctcagggtcc 240 aagaggttga tggcactcca agagaaatat ggactggttg agagggcaga gaccaggctc 300 tcaatcactc ctgtgagggt tgcgcagagc cttcccactt ggacatgtgc tgcagcagca 360 gccttgaagg agtatctccc tgtggggcca gccgtcatga acctgaaggt cgagaattat 420 ccccctgaga tgatgtgcat ggcctttgga tccctgattc caactgcggg ggtatctgaa 480 gccacaacca agaccctgat ggaggcctac tctctgtggc aagatgcctt caccaagact 540 atcaatgtga agatgcgcgg agccagcaag acagaagttt acaactcctt cagggaccct 600 cttcatgctg ctgtgaactc tgtcttcttt cccaatgatg ttcgggtaaa gtggctgaag 660 gccaagggga tccttggccc agatggggtc cccagcagag ctgctgaggt tgctgctgct 720 gcttacagaa acctgtaa 738 <210> 10 <211> 676 <212> PRT <213> Unknown <220> <223> Gn-Fc <400> 10 Asp Val Ala Gln Ala Ala Asp Ser Gly Pro Ile Ile Cys Ala Gly Pro 1 5 10 15 Ile His Ser Asn Lys Ser Ala Asp Ile Pro His Leu Leu Gly Tyr Ser 20 25 30 Glu Lys Ile Cys Gln Ile Asp Arg Leu Ile His Val Ser Ser Trp Leu 35 40 45 Arg Asn His Ser Gln Phe Gln Gly Tyr Val Gly Gln Arg Gly Gly Arg 50 55 60 Ser Gln Val Ser Tyr Tyr Pro Ala Glu Asn Ser Tyr Ser Arg Trp Ser 65 70 75 80 Gly Leu Leu Ser Pro Cys Asp Ala Asp Trp Leu Gly Met Leu Val Val 85 90 95 Lys Lys Ala Lys Gly Ser Asp Met Ile Val Pro Gly Pro Ser Tyr Lys 100 105 110 Gly Lys Val Phe Phe Glu Arg Pro Thr Phe Asp Gly Tyr Val Gly Trp 115 120 125 Gly Cys Gly Ser Gly Lys Ser Arg Thr Glu Ser Gly Glu Leu Cys Ser 130 135 140 Ser Asp Ser Gly Thr Ser Ser Gly Leu Leu Pro Ser Asp Arg Val Leu 145 150 155 160 Trp Ile Gly Asp Val Ala Cys Gln Pro Met Thr Pro Ile Pro Glu Glu 165 170 175 Thr Phe Leu Glu Leu Lys Ser Phe Ser Gln Ser Glu Phe Pro Asp Ile 180 185 190 Cys Lys Ile Asp Gly Ile Val Phe Asn Gln Cys Glu Gly Glu Ser Leu 195 200 205 Pro Gln Pro Phe Asp Val Ala Trp Met Asp Val Gly His Ser His Lys 210 215 220 Ile Ile Met Arg Glu His Lys Thr Lys Trp Val Gln Glu Ser Ser Ser 225 230 235 240 Lys Asp Phe Val Cys Tyr Lys Glu Gly Thr Gly Pro Cys Ser Glu Ser 245 250 255 Glu Glu Lys Thr Cys Lys Thr Ser Gly Ser Cys Arg Gly Asp Met Gln 260 265 270 Phe Cys Lys Val Ala Gly Cys Glu His Gly Glu Glu Ala Ser Glu Ala 275 280 285 Lys Cys Arg Cys Ser Leu Val His Lys Pro Gly Glu Val Val Val Ser 290 295 300 Tyr Gly Gly Met Arg Val Arg Pro Lys Cys Tyr Gly Phe Ser Arg Met 305 310 315 320 Met Ala Thr Leu Glu Val Asn Gln Pro Glu Gln Arg Ile Gly Gln Cys 325 330 335 Thr Gly Cys His Leu Glu Cys Ile Asn Gly Gly Val Arg Leu Ile Thr 340 345 350 Leu Thr Ser Glu Leu Lys Ser Ala Thr Val Cys Ala Ser His Phe Cys 355 360 365 Ser Ser Ala Thr Ser Gly Lys Lys Ser Thr Glu Ile Gln Phe His Ser 370 375 380 Gly Ser Leu Val Gly Lys Thr Ala Ile His Val Lys Gly Ala Leu Val 385 390 395 400 Asp Gly Thr Glu Phe Thr Phe Glu Gly Ser Cys Met Phe Pro Asp Gly 405 410 415 Cys Asp Ala Val Asp Cys Thr Phe Cys Arg Glu Phe Leu Lys Asn Pro 420 425 430 Gln Cys Tyr Pro Ala Lys Lys Gly Gln Ala Gly Gln Glu Pro Lys Ser 435 440 445 Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu 450 455 460 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 465 470 475 480 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 485 490 495 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 500 505 510 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 515 520 525 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 530 535 540 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 545 550 555 560 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 565 570 575 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 580 585 590 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 595 600 605 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 610 615 620 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 625 630 635 640 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 645 650 655 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 660 665 670 Ser Pro Gly Lys 675 <210> 11 <211> 711 <212> PRT <213> Unknown <220> <223> Gc-Fc <400> 11 Asp Val Ala Gln Ala Ala Cys Asp Glu Met Val His Ala Asp Ser Lys 1 5 10 15 Leu Val Ser Cys Arg Gln Gly Ser Gly Asn Met Lys Glu Cys Val Thr 20 25 30 Thr Gly Arg Ala Leu Leu Pro Ala Val Asn Pro Gly Gln Glu Ala Cys 35 40 45 Leu His Phe Thr Ala Pro Gly Ser Pro Asp Ser Lys Cys Leu Lys Ile 50 55 60 Lys Val Lys Arg Ile Asn Leu Lys Cys Lys Lys Ser Ser Ser Tyr Phe 65 70 75 80 Val Pro Asp Ala Arg Ser Arg Cys Thr Ser Val Arg Arg Cys Arg Trp 85 90 95 Ala Gly Asp Cys Gln Ser Gly Cys Pro Pro His Phe Thr Ser Asn Ser 100 105 110 Phe Ser Asp Asp Trp Ala Gly Lys Met Asp Arg Ala Gly Leu Gly Phe 115 120 125 Ser Gly Cys Ser Asp Gly Cys Gly Gly Ala Ala Cys Gly Cys Phe Asn 130 135 140 Ala Ala Pro Ser Cys Ile Phe Trp Arg Lys Trp Val Glu Asn Pro His 145 150 155 160 Gly Ile Ile Trp Lys Val Ser Pro Cys Ala Ala Trp Val Pro Ser Ala 165 170 175 Val Ile Glu Leu Thr Met Pro Ser Gly Glu Val Arg Thr Phe His Pro 180 185 190 Met Ser Gly Ile Pro Thr Gln Val Phe Lys Gly Val Ser Val Thr Tyr 195 200 205 Leu Gly Ser Asp Met Glu Val Ser Gly Leu Thr Asp Leu Cys Glu Ile 210 215 220 Glu Glu Leu Lys Ser Lys Lys Leu Ala Leu Ala Pro Cys Asn Gln Ala 225 230 235 240 Gly Met Gly Val Val Gly Lys Val Gly Glu Ile Gln Cys Ser Ser Glu 245 250 255 Glu Ser Ala Arg Thr Ile Lys Lys Asp Gly Cys Ile Trp Asn Ala Asp 260 265 270 Leu Val Gly Ile Glu Leu Arg Val Asp Asp Ala Val Cys Tyr Ser Lys 275 280 285 Ile Thr Ser Val Glu Ala Val Ala Asn Tyr Ser Ala Ile Pro Thr Thr 290 295 300 Ile Gly Gly Leu Arg Phe Glu Arg Ser His Asp Ser Gln Gly Lys Ile 305 310 315 320 Ser Gly Ser Pro Leu Asp Ile Thr Ala Ile Arg Gly Ser Phe Ser Val 325 330 335 Asn Tyr Arg Gly Leu Arg Leu Ser Leu Ser Glu Ile Thr Ala Thr Cys 340 345 350 Thr Gly Glu Val Thr Asn Val Ser Gly Cys Tyr Ser Cys Met Thr Gly 355 360 365 Ala Lys Val Ser Ile Lys Leu His Ser Ser Lys Asn Ser Thr Ala His 370 375 380 Val Arg Cys Lys Gly Asp Glu Thr Ala Phe Ser Val Leu Glu Gly Val 385 390 395 400 His Ser Tyr Thr Val Ser Leu Ser Phe Asp His Ala Val Val Asp Glu 405 410 415 Gln Cys Gln Leu Asn Cys Gly Gly His Glu Ser Gln Val Thr Leu Lys 420 425 430 Gly Asn Leu Ile Phe Leu Asp Val Pro Lys Phe Val Asp Gly Ser Tyr 435 440 445 Met Gln Thr Tyr His Ser Thr Val Pro Thr Gly Ala Asn Ile Pro Ser 450 455 460 Pro Thr Asp Trp Leu Asn Ala Leu Phe Gly Asn Gly Leu Ser Arg Glu 465 470 475 480 Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro 485 490 495 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 500 505 510 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 515 520 525 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 530 535 540 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 545 550 555 560 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 565 570 575 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 580 585 590 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 595 600 605 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 610 615 620 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 625 630 635 640 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 645 650 655 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 660 665 670 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 675 680 685 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 690 695 700 Leu Ser Leu Ser Pro Gly Lys 705 710 <210> 12 <211> 245 <212> PRT <213> Unknown <220> <223> NP <400> 12 Met Ser Glu Trp Ser Arg Ile Ala Val Glu Phe Gly Glu Gln Gln Leu 1 5 10 15 Asn Leu Ser Glu Leu Glu Asp Phe Ala Arg Glu Leu Ala Tyr Glu Gly 20 25 30 Leu Asp Pro Ala Leu Ile Ile Lys Lys Leu Lys Glu Thr Gly Gly Asp 35 40 45 Asp Trp Val Lys Asp Thr Lys Phe Ile Ile Val Phe Ala Leu Thr Arg 50 55 60 Gly Asn Lys Ile Val Lys Ala Ser Gly Lys Met Ser Asn Ser Gly Ser 65 70 75 80 Lys Arg Leu Met Ala Leu Gln Glu Lys Tyr Gly Leu Val Glu Arg Ala 85 90 95 Glu Thr Arg Leu Ser Ile Thr Pro Val Arg Val Ala Gln Ser Leu Pro 100 105 110 Thr Trp Thr Cys Ala Ala Ala Ala Ala Leu Lys Glu Tyr Leu Pro Val 115 120 125 Gly Pro Ala Val Met Asn Leu Lys Val Glu Asn Tyr Pro Pro Glu Met 130 135 140 Met Cys Met Ala Phe Gly Ser Leu Ile Pro Thr Ala Gly Val Ser Glu 145 150 155 160 Ala Thr Thr Lys Thr Leu Met Glu Ala Tyr Ser Leu Trp Gln Asp Ala 165 170 175 Phe Thr Lys Thr Ile Asn Val Lys Met Arg Gly Ala Ser Lys Thr Glu 180 185 190 Val Tyr Asn Ser Phe Arg Asp Pro Leu His Ala Ala Val Asn Ser Val 195 200 205 Phe Phe Pro Asn Asp Val Arg Val Lys Trp Leu Lys Ala Lys Gly Ile 210 215 220 Leu Gly Pro Asp Gly Val Pro Ser Arg Ala Ala Glu Val Ala Ala Ala 225 230 235 240 Ala Tyr Arg Asn Leu 245 <110> SNU R&DB Foundation <120> Vaccine Composition for SFTS virus <130> PP19-000-SNU-CHO <160> 12 <170> KoPatentIn 3.0 <210> 1 <211> 438 <212> PRT <213> Unknown < 220> <223> Extracellular domain of Gn protein of SFTS virus <400> 1 Asp Ser Gly Pro Ile Ile Cys Ala Gly Pro Ile His Ser Asn Lys Ser 1 5 10 15 Ala Asp Ile Pro His Leu Leu Gly Tyr Ser Glu Lys Ile Cys Gln Ile 20 25 30 Asp Arg Leu Ile His Val Ser Ser Trp Leu Arg Asn His Ser Gln Phe 35 40 45 Gln Gly Tyr Val Gly Gln Arg Gly Gly Arg Ser Gln Val Ser Tyr Tyr 50 55 60 Pro Ala Glu Asn Ser Tyr Ser Arg Trp Ser Gly Leu Leu Ser Pro Cys 65 70 75 80 Asp Ala Asp Trp Leu Gly Met Leu Val Val Lys Lys Ala Lys Gly Ser 85 90 95 Asp Met Ile Val Pro Gly Pro Ser Tyr Lys Gly Lys Val Phe Phe Glu 100 105 110 Arg Pro Thr Phe Asp Gly Tyr Val Gly Trp Gly Cys Gly Ser Gly Lys 115 120 125 Ser Arg Thr Glu Ser Gly Glu Leu Cys Ser Ser Asp Ser Gly Thr Ser 130 135 140 Ser Gly Leu Leu Pro Ser Asp Arg Val Leu Trp Ile Gly Asp Val Ala 145 150 155 160 Cys Gln Pro Met Thr Pro Ile Pro Glu Glu Thr Phe Leu Glu Leu Lys 165 170 175 Ser Phe Ser Gln Ser Glu Phe Pro Asp Ile Cys Lys Ile Asp Gly Ile 180 185 190 Val Phe Asn Gln Cys Glu Gly Glu Ser Leu Pro Gln Pro Phe Asp Val 195 200 205 Ala Trp Met Asp Val Gly His Ser His Lys Ile Ile Met Arg Glu His 210 215 220 Lys Thr Lys Trp Val Gln Glu Ser Ser Ser Lys Asp Phe Val Cys Tyr 225 230 235 240 Lys Glu Gly Thr Gly Pro Cys Ser Glu Ser Glu Lys Thr Cys Lys 245 250 255 Thr Ser Gly Ser Cys Arg Gly Asp Met Gln Phe Cys Lys Val Ala Gly 260 265 270 Cys Glu His Gly Glu Glu Ala Ser Glu Ala Lys Cys Arg Cys Ser Leu 275 280 285 Val His Lys Pro Gly Glu Val Val Val Ser Tyr Gly Gly Met Arg Val 290 295 300 Arg Pro Lys Cys Tyr Gly Phe Ser Arg Met Met Ala Thr Leu Glu Val 305 310 315 320 Asn Gln Pro Glu Gln Arg Ile Gly Gln Cys Thr Gly Cys His Leu Glu 325 330 335 Cys Ile Asn Gly Gly Val Arg Leu Ile Thr Leu Thr Ser Glu Leu Lys 340 345 350 Ser Ala Thr Val Cys Ala Ser His Phe Cys Ser Ser Ala Thr Ser Gly 355 360 365 Lys Lys Ser Thr Glu Ile Gln Phe His Ser Gly Ser Leu Val Gly Lys 370 375 380 Thr Ala Ile His Val Lys Gly Ala Leu Val Asp Gly Thr Glu Phe Thr 385 390 395 400 Phe Glu Gly Ser Cys Met Phe Pro Asp Gly Cys Asp Ala Val Asp Cys 405 410 415 Thr Phe Cys Arg Glu Phe Leu Lys Asn Pro Gln Cys Tyr Pro Ala Lys 420 425 430 Lys Gly Gln Ala Gly Gln 435 <210> 2 <211> 473 <212> PRT <213> Unknown <220> <223> Extracellular domain of Gc protein of SFTS virus <400> 2 Cys Asp Glu Met Val His Ala Asp Ser Lys Leu Val Ser Cys Arg Gln 1 5 10 15 Gly Ser Gly Asn Met Lys Glu Cys Val Thr Thr Gly Arg Ala Leu Leu 20 25 30 Pro Ala Val Asn Pro Gly Gln Glu Ala Cys Leu His Phe Thr Ala Pro 35 40 45 Gly Ser Pro Asp Ser Lys Cys Leu Lys Ile Lys Val Lys Arg Ile Asn 50 55 60 Leu Lys Cys Lys Lys Ser Ser Ser Tyr Phe Val Pro Asp Ala Arg Ser 65 70 75 80 Arg Cys Thr Ser Val Arg Arg Cys Arg Trp Ala Gly Asp Cys Gln Ser 85 90 95 Gly Cys Pro Pro His Phe Thr Ser Asn Ser Phe Ser Asp Asp Trp Ala 100 105 110 Gly Lys Met Asp Arg Ala Gly Leu Gly Phe Ser Gly Cys Ser Asp Gly 115 120 125 Cys Gly Gly Ala Ala Cys Gly Cys Phe Asn Ala Ala Pro Ser Cys Ile 130 135 140 Phe Trp Arg Lys Trp Val Glu Asn Pro His Gly Ile Ile Trp Lys Val 145 150 155 160 Ser Pro Cys Ala Ala Trp Val Pro Ser Ala Val Ile Glu Leu Thr Met 165 170 175 Pro Ser Gly Glu Val Arg Thr Phe His Pro Met Ser Gly Ile Pro Thr 180 185 190 Gln Val Phe Lys Gly Val Ser Val Thr Tyr Leu Gly Ser Asp Met Glu 195 200 205 Val Ser Gly Leu Thr Asp Leu Cys Glu Ile Glu Glu Leu Lys Ser Lys 210 215 220 Lys Leu Ala Leu Ala Pro Cys Asn Gln Ala Gly Met Gly Val Val Gly 225 230 235 240 Lys Val Gly Glu Ile Gln Cys Ser Ser Glu Glu Ser Ala Arg Thr Ile 245 250 255 Lys Lys Asp Gly Cys Ile Trp Asn Ala Asp Leu Val Gly Ile Glu Leu 260 265 270 Arg Val Asp Asp Ala Val Cys Tyr Ser Lys Ile Thr Ser Val Glu Ala 275 280 285 Val Ala Asn Tyr Ser Ala Ile Pro Thr Thr Ile Gly Gly Leu Arg Phe 290 295 300 Glu Arg Ser His Asp Ser Gln Gly Lys Ile Ser Gly Ser Pro Leu Asp 305 310 315 320 Ile Thr Ala Ile Arg Gly Ser Phe Ser Val Asn Tyr Arg Gly Leu Arg 325 330 335 Leu Ser Leu Ser Glu Ile Thr Ala Thr Cys Thr Gly Glu Val Thr Asn 340 345 350 Val Ser Gly Cys Tyr Ser Cys Met Thr Gly Ala Lys Val Ser Ile Lys 355 360 365 Leu His Ser Ser Lys Asn Ser Thr Ala His Val Arg Cys Lys Gly Asp 370 375 380 Glu Thr Ala Phe Ser Val Leu Glu Gly Val His Ser Tyr Thr Val Ser 385 390 395 400 Leu Ser Phe Asp His Ala Val Val Asp Glu Gln Cys Gln Leu Asn Cys 405 410 415 Gly Gly His Glu Ser Gln Val Thr Leu Lys Gly Asn Leu Ile Phe Leu 420 425 430 Asp Val Pro Lys Phe Val Asp Gly Ser Tyr Met Gln Thr Tyr His Ser 435 440 445 Thr Val Pro Thr Gly Ala Asn Ile Pro Ser Pro Thr Asp Trp Leu Asn 450 455 460 Ala Leu Phe Gly Asn Gly Leu Ser Arg 465 470 <210> 3 < 211> 245 <212> PRT <213> Unknown <220> <223> NP protein of SFTS virus <400> 3 Met Ser Glu Trp Ser Arg Ile Ala Val Glu Phe Gly Glu Gln Gln Leu 1 5 10 15 Asn Leu Ser Glu Leu Glu Asp Phe Ala Arg Glu Leu Ala Tyr Glu Gly 20 25 30 Leu Asp Pro Ala Leu Ile Ile Lys Lys Leu Lys Glu Thr Gly Gly Asp 35 40 45 Asp Trp Val Lys Asp Thr Lys Phe Ile Ile Val Phe Ala Leu Thr Arg 50 55 60 Gly Asn Lys Ile Val Lys Ala Ser Gly Lys Met Ser Asn Ser Gly Ser 65 70 75 80 Lys Arg Leu Met Ala Leu Gln Glu Lys Tyr Gly Leu Val Glu Arg Ala 85 90 95 Glu Thr Arg Leu Ser Ile Thr Pro Val Arg Val Ala Gln Ser Leu Pro 100 105 110 Thr Trp Thr Cys Ala Ala Ala Ala Ala Leu Lys Glu Tyr Leu Pro Val 115 120 125 Gly Pro Ala Val Met Asn Leu Lys Val Glu Asn Tyr Pro Pro Glu Met 130 135 140 Met Cys Met Ala Phe Gly Ser Leu Ile Pro Thr Ala Gly Val Ser Glu 145 150 155 160 Ala Thr Thr Lys Thr Leu Met Glu Ala Tyr Ser Leu Trp Gln Asp Ala 165 170 175 Phe Thr Lys Thr Ile Asn Val Lys Met Arg Gly Ala Ser Lys Thr Glu 180 185 190 Val Tyr Asn Ser Phe Arg Asp Pro Leu His Ala Ala Val Asn Ser Val 195 200 205 Phe Phe Pro Asn Asp Val Arg Val Lys Trp Leu Lys Ala Lys Gly Ile 210 215 220 Leu Gly Pro Asp Gly Val Pro Ser Arg Ala Ala Glu Val Ala Ala Ala 225 230 235 240 Ala Tyr Arg Asn Leu 245 <210> 4 <211> 1299 <212> DNA <213> Unknown <220> <223> gene encoding excellular protein domain of Gn of SFTS virus <400> 4 gactctggac ctattatctg tgctggacct attcattcaa acaaatctgc tgacatccct 60 catctgctgg gctactccga aaaaatctgc cagattgatc gactgatcca cgtgagctcc 120 tggctgcgga accatagcca gttccaggga tacgtcggac agagggg cgg gcgctctcag 180 gtgagttact atccagccga gaacagctac agccggtggt ccggactgct gtctccatgt 240 gacgcagatt ggct gggaat gctggtggtc aagaaagcta agggctcaga tatgattgtc 300 cccggcccta gctacaaggg gaaagtgttc tttgaacgcc cc accttcga cggctatgtg 360 ggctgggggt gcggatcagg caaaagccga acagagtccg gagaactgtg cagcagcgac 420 tctggaactt caagcggcct gctgcctagc gatagggtcc tgtggattgg cgacgtggcc 480 tgccagccaa tgaccccaat ccccgaggaa acatttctgg agctgaagag tttctcacag 540 a gcgaatttc cagacatctg caaaattgac ggcatcgtgt tcaaccagtg tgagggggaa 600 agcctgcctc agccatttga tgtcgcttgg atggacgtgg gccactccca taagatcatt 660 atgcgcgagc acaagactaa atgggtccag gaatcctcta gtaaggattt cgtgtgctac 7 20 aaagagggga ccggaccctg ttccgaatct gaggaaaaga cttgcaaaac cagtgggtca 780 tgtcggggag acatgcagtt ttgcaaggtg gctggctgg agcacgggga ggaagcctct 840 gaagctaaat gcagatgtag tctggtccat aaacccggcg aggtggtcgt gagttacgga 900 ggcatgcggg tgagacctaa atgctatggg ttcagcagaa tgatggcaac cctggaggtg 960 aac cagcctg aacagaggat cggacagtgc acaggctgtc acctggagtg tattaatggg 1020 ggagtccgac tgatcaccct gacaagtgaa ctgaagtcag caacagtgg cgcctctcat 1080 ttctgttcaa gcgccactag cggcaagaaa tccaccgaga ttcagtttca cagcgggtcc 1140 ctggtgggaa agactgctat ccatgtcaaa ggagcactgg tggatggcac agagttcact 1200 tttgaagggt cctgcatgtt tccagacgga tgtgatgcag tggactgcac attctgtcgc 1260 gagtttctga agaatcccca gtgctatcct gccaagaaa 1299 <210> 5 <211> 1419 <212> DNA <213> Unknown <220> <223> gene encoding excellular domain of Gc protein of SFTS virus <400> 5 tg cgatgaaa tggtccacgc cgatagcaaa ctggtcagct gtaggcaggg aagcgggaac 60 atgaaggaat gcgtcacaac cggaagagct ctgctgccag cagtgaaccc tggacaggag 120 gcctgcctgc acttcacagc tcctggaagt ccagactcaa aatgcctgaa gatcaaagtg 180 aagcggatta atctgaagtg taagaaaagc tcctcttact t tgtgcccga cgcaaggtca 240 cgctgcacta gcgtccggag atgtagatgg gcaggcgatt gccagagcgg atgtccacct 300 catttcacct ctaacagttt ttcagacgat tgggcaggca agatggacag ggcaggactg 360 gggttcagcg gatgctccga tggatgtgga ggagca gctt gcggatgttt caacgcagcc 420 ccctcctgca tcttttggcg caaatgggtg gagaatcctc acggcatcat ttggaaggtc 480 tccccttgtg ctgcatgggt gccatctgcc gtcatcgagc tgacaatgcc cagcggcgaa 540 gtgagaactt tccatccaat gtccgggatt cccacccagg tctttaaggg agtgtctgtc 600 acatatctgg gcagcgacat ggaggtgtcc gggctgactg atctgtgcga aatc gaggaa 660 ctgaaatcca agaaactggc cctggctcct tgtaatcagg caggaatggg agtggtcggc 720 aaggtcgggg agattcagtg cagttcagag gaaagcgcac gcaccatcaa gaaagacggg 780 tgtatttgga acgccgatct ggtgggaatc gagctgcgag tggacgatgc tgtctgctac 840 tccaaaatta catctgtgga agcagtcgcc aattattccg ctatccctac cacaattggc 900 gtggctgcta ttcatgtatg 1080 accggggcaa aagtgagtat taagctgcac agctccaaaa actcaacagc tcatgtgcgc 1140 tgtaagggag acgagactgc attctctgtg ctggaaggcg tccacagtta cacagtgtcc 1200 ctgtcttttg accatgccgt ggtcgatgag cagtgcc agc tgaactgtgg gggacacgaa 1260 agccaagtga ctctgaaagg caatctgatc ttcctggacg tgccaaagtt tgtcgatggg 1320 tcatacatgc agacctatca tagcactgtg cccaccggcg ccaatattcc atctcccaca 1380 gattggctga acgctctgtt tgggaatgga ctgagtcgg 1419 <210> 6 <211> 60 <212> DNA <213> Unknown <220> <223> gene encoding signal peptide <400> 6 atggagacag acacactcct g ctatgggta ctgctgctct gggttccagg ttccactggt 60 60 < 210> 7 <211> 654 <212> DNA <213> Unknown <220> <223> gene encoding human Fc <400> 7 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg t ggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagca atgggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ccccgggtaa atga 654 <210> 8 <211> 60 <212> DNA <213> Unknown <220> <223> gene encoding hinge region <400> 8 ggccaggccg gccaggagcc caaatctagc gacaaaactc acacaagccc accgagccca 60 60 <2 10> 9 < 211 > 738 <212> DNA <213> Unknown <220> <223> gene encoding NP protein of SFTS virus <400> 9 atgtcggagt ggtccaggat tgcagtggag tttggtgagc agcagctcaa tttgtctgag 60 cttgaggatt tcgcgagaga actggcctat gaaggccttg accctg cttt gatcatcaag 120 aagctgaagg agacaggtgg agatgattgg gtgaaggata caaagttcat cattgtcttt 180 gccctgactc gaggcaacaa gatcgtcaag gcatcaggga aaatgtcaaa ctcagggtcc 240 aagaggttga tggcactcca agagaaatat ggactggttg agagggcaga gaccaggctc 300 tcaatcactc ctgtgagggt tgcgcagagc cttcccactt ggacatgtgc tgcagcagca 360 gccttga agg agtatctccc tgtggggcca gccgtcatga acctgaaggt cgagaattat 420 ccccctgaga tgatgtgcat ggcctttgga tccctgattc caactgcggg ggtatctgaa 480 gccacaacca agaccctgat ggaggcctac tctctgtggc aagatgcctt caccaagact 540 atcaat gtga agatgcgcgg agccagcaag acagaagttt acaactcctt cagggaccct 600 cttcatgctg ctgtgaactc tgtcttcttt cccaatgatg ttcgggtaaa gtggctgaag 660 gccaagggga tccttggccc agatggggtc cccagcagag ctgctgaggt tgctgctgct 720 gcttacagaa acctgtaa 738 <210> 10 <211> 676 <212> PRT <213> Unknown <220 > <223> Gn-Fc <400> 10 Asp Val Ala Gln Ala Ala Asp Ser Gly Pro Ile Ile Cys Ala Gly Pro 1 5 10 15 Ile His Ser Asn Lys Ser Ala Asp Ile Pro His Leu Leu Gly Tyr Ser 20 25 30 Glu Lys Ile Cys Gln Ile Asp Arg Leu Ile His Val Ser Ser Trp Leu 35 40 45 Arg Asn His Ser Gln Phe Gln Gly Tyr Val Gly Gln Arg Gly Gly Arg 50 55 60 Ser Gln Val Ser Tyr Tyr Pro Ala Glu Asn Ser Tyr Ser Arg Trp Ser 65 70 75 80 Gly Leu Leu Ser Pro Cys Asp Ala Asp Trp Leu Gly Met Leu Val Val 85 90 95 Lys Lys Ala Lys Gly Ser Asp Met Ile Val Pro Gly Pro Ser Tyr Lys 100 105 110 Gly Lys Val Phe Phe Glu Arg Pro Thr Phe Asp Gly Tyr Val Gly Trp 115 120 125 Gly Cys Gly Ser Gly Lys Ser Arg Thr Glu Ser Gly Glu Leu Cys Ser 130 135 140 Ser Asp Ser Gly Thr Ser Ser Gly Leu Leu Pro Ser Asp Arg Val Leu 145 150 155 160 Trp Ile Gly Asp Val Ala Cys Gln Pro Met Thr Pro Ile Pro Glu Glu 165 170 175 Thr Phe Leu Glu Leu Lys Ser Phe Ser Gln Ser Glu Phe Pro Asp Ile 180 185 190 Cys Lys Ile Asp Gly Ile Val Phe Asn Gln Cys Glu Gly Glu Ser Leu 195 200 205 Pro Gln Pro Phe Asp Val Ala Trp Met Asp Val Gly His Ser His Lys 210 215 220 Ile Ile Met Arg Glu His Lys Thr Lys Trp Val Gln Glu Ser Ser Ser Ser 225 230 235 240 Lys Asp Phe Val Cys Tyr Lys Glu Gly Thr Gly Pro Cys Ser Glu Ser 245 250 255 Glu Glu Lys Thr Cys Lys Thr Ser Gly Ser Cys Arg Gly Asp Met Gln 260 265 270 Phe Cys Lys Val Ala Gly Cys Glu His Gly Glu Glu Ala Ser Glu Ala 275 280 285 Lys Cys Arg Cys Ser Leu Val His Lys Pro Gly Glu Val Val Val Ser 290 295 300 Tyr Gly Gly Met Arg Val Arg Pro Lys Cys Tyr Gly Phe Ser Arg Met 305 310 315 320 Met Ala Thr Leu Glu Val Asn Gln Pro Glu Gln Arg Ile Gly Gln Cys 325 330 335 Thr Gly Cys His Leu Glu Cys Ile Asn Gly Gly Val Arg Leu Ile Thr 340 345 350 Leu Thr Ser Glu Leu Lys Ser Ala Thr Val Cys Ala Ser His Phe Cys 355 360 365 Ser Ser Ala Thr Ser Gly Lys Lys Ser Thr Glu Ile Gln Phe His Ser 370 375 380 Gly Ser Leu Val Gly Lys Thr Ala Ile His Val Lys Gly Ala Leu Val 385 390 395 400 Asp Gly Thr Glu Phe Thr Phe Glu Gly Ser Cys Met Phe Pro Asp Gly 405 410 415 Cys Asp Ala Val Asp Cys Thr Phe Cys Arg Glu Phe Leu Lys Asn Pro 420 425 430 Gln Cys Tyr Pro Ala Lys Lys Gly Gln Ala Gly Gln Glu Pro Lys Ser 435 440 445 Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu 450 455 460 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 465 470 475 480 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 485 490 495 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 500 505 510 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 515 520 525 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 530 535 540 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 545 550 555 560 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 565 570 575 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 580 585 590 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 595 600 605 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 610 615 620 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 625 630 635 640 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 645 650 655 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 660 665 670 Ser Pro Gly Lys 675 <210> 11 <211> 711 <212> PRT <213> Unknown <220> <223> Gc-Fc <400> 11 Asp Val Ala Gln Ala Ala Cys Asp Glu Met Val His Ala Asp Ser Lys 1 5 10 15 Leu Val Ser Cys Arg Gln Gly Ser Gly Asn Met Lys Glu Cys Val Thr 20 25 30 Thr Gly Arg Ala Leu Leu Pro Ala Val Asn Pro Gly Gln Glu Ala Cys 35 40 45 Leu His Phe Thr Ala Pro Gly Ser Pro Asp Ser Lys Cys Leu Lys Ile 50 55 60 Lys Val Lys Arg Ile Asn Leu Lys Cys Lys Lys Ser Ser Ser Tyr Phe 65 70 75 80 Val Pro Asp Ala Arg Ser Arg Cys Thr Ser Val Arg Arg Cys Arg Trp 85 90 95 Ala Gly Asp Cys Gln Ser Gly Cys Pro Pro His Phe Thr Ser Asn Ser 100 105 110 Phe Ser Asp Asp Trp Ala Gly Lys Met Asp Arg Ala Gly Leu Gly Phe 115 120 125 Ser Gly Cys Ser Asp Gly Cys Gly Gly Ala Ala Cys Gly Cys Phe Asn 130 135 140 Ala Ala Pro Ser Cys Ile Phe Trp Arg Lys Trp Val Glu Asn Pro His 145 150 155 160 Gly Ile Ile Trp Lys Val Ser Pro Cys Ala Ala Trp Val Pro Ser Ala 165 170 175 Val Ile Glu Leu Thr Met Pro Ser Gly Glu Val Arg Thr Phe His Pro 180 185 190 Met Ser Gly Ile Pro Thr Gln Val Phe Lys Gly Val Ser Val Thr Tyr 195 200 205 Leu Gly Ser Asp Met Glu Val Ser Gly Leu Thr Asp Leu Cys Glu Ile 210 215 220 Glu Glu Leu Lys Ser Lys Lys Leu Ala Leu Ala Pro Cys Asn Gln Ala 225 230 235 240 Gly Met Gly Val Val Gly Lys Val Gly Glu Ile Gln Cys Ser Ser Glu 245 250 255 Glu Ser Ala Arg Thr Ile Lys Lys Asp Gly Cys Ile Trp Asn Ala Asp 260 265 270 Leu Val Gly Ile Glu Leu Arg Val Asp Asp Ala Val Cys Tyr Ser Lys 275 280 285 Ile Thr Ser Val Glu Ala Val Ala Asn Tyr Ser Ala Ile Pro Thr Thr 290 295 300 Ile Gly Gly Leu Arg Phe Glu Arg Ser His Asp Ser Gln Gly Lys Ile 305 310 315 320 Ser Gly Ser Pro Leu Asp Ile Thr Ala Ile Arg Gly Ser Phe Ser Val 325 330 335 Asn Tyr Arg Gly Leu Arg Leu Ser Leu Ser Glu Ile Thr Ala Thr Cys 340 345 350 Thr Gly Glu Val Thr Asn Val Ser Gly Cys Tyr Ser Cys Met Thr Gly 355 360 365 Ala Lys Val Ser Ile Lys Leu His Ser Ser Lys Asn Ser Thr Ala His 370 375 380 Val Arg Cys Lys Gly Asp Glu Thr Ala Phe Ser Val Leu Glu Gly Val 385 390 395 400 His Ser Tyr Thr Val Ser Leu Ser Phe Asp His Ala Val Val Asp Glu 405 410 415 Gln Cys Gln Leu Asn Cys Gly Gly His Glu Ser Gln Val Thr Leu Lys 420 425 430 Gly Asn Leu Ile Phe Leu Asp Val Pro Lys Phe Val Asp Gly Ser Tyr 435 440 445 Met Gln Thr Tyr His Ser Thr Val Pro Thr Gly Ala Asn Ile Pro Ser 450 455 460 Pro Thr Asp Trp Leu Asn Ala Leu Phe Gly Asn Gly Leu Ser Arg Glu 465 470 475 480 Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro 485 490 495 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 500 505 510 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 515 520 525 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 530 535 540 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 545 550 555 560 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 565 570 575 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 580 585 590 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 595 600 605 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 610 615 620 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 625 630 635 640 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 645 650 655 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 660 665 670 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 675 680 685 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 690 695 700 Leu Ser Leu Ser Pro Gly Lys 705 710 <210> 12 <211> 245 <212> PRT <213> Unknown <220> <223> NP < 400> 12 Met Ser Glu Trp Ser Arg Ile Ala Val Glu Phe Gly Glu Gln Gln Leu 1 5 10 15 Asn Leu Ser Glu Leu Glu Asp Phe Ala Arg Glu Leu Ala Tyr Glu Gly 20 25 30 Leu Asp Pro Ala Leu Ile Ile Lys Lys Leu Lys Glu Thr Gly Gly Asp 35 40 45 Asp Trp Val Lys Asp Thr Lys Phe Ile Ile Val Phe Ala Leu Thr Arg 50 55 60 Gly Asn Lys Ile Val Lys Ala Ser Gly Lys Met Ser Asn Ser Gly Ser 65 70 75 80 Lys Arg Leu Met Ala Leu Gln Glu Lys Tyr Gly Leu Val Glu Arg Ala 85 90 95 Glu Thr Arg Leu Ser Ile Thr Pro Val Arg Val Ala Gln Ser Leu Pro 100 105 110 Thr Trp Thr Cys Ala Ala Ala Ala Ala Leu Lys Glu Tyr Leu Pro Val 115 120 125 Gly Pro Ala Val Met Asn Leu Lys Val Glu Asn Tyr Pro Pro Glu Met 130 135 140 Met Cys Met Ala Phe Gly Ser Leu Ile Pro Thr Ala Gly Val Ser Glu 145 150 155 160 Ala Thr Thr Lys Thr Leu Met Glu Ala Tyr Ser Leu Trp Gln Asp Ala 165 170 175 Phe Thr Lys Thr Ile Asn Val Lys Met Arg Gly Ala Ser Lys Thr Glu 180 185 190 Val Tyr Asn Ser Phe Arg Asp Pro Leu His Ala Ala Val Asn Ser Val 195 200 205 Phe Phe Pro Asn Asp Val Arg Val Lys Trp Leu Lys Ala Lys Gly Ile 210 215 220 Leu Gly Pro Asp Gly Val Pro Ser Arg Ala Ala Glu Val Ala Ala Ala 225 230 235 240 Ala Tyr Arg Asn Leu 245
Claims (8)
상기 Gn 단백질은 사람 항체의 Fc 부위에 융합된 형태인,
SFTS 바이러스에 대한 백신 조성물.
A mixture of the extracellular domain of the Gn protein (SEQ ID NO: 1) and the full-length NP protein (SEQ ID NO: 3) as an active ingredient,
The Gn protein is in the form of a fusion to the Fc region of a human antibody,
Vaccine composition against SFTS virus.
상기 Gn 단백질의 세포외 도메인과 사람 항체의 Fc 부위는, 이들 각 단백질이 서로 간에 3차원 구조 형성을 방해하지 않도록 2~15개 아미노산을 가진 힌지 서열이 이들 단백질 사이에 게재되어, 융합되어 있는 것을 특징으로 하는 백신 조성물.
In paragraph 1,
The extracellular domain of the Gn protein and the Fc region of the human antibody are fused with a hinge sequence of 2 to 15 amino acids interposed between these proteins so as not to interfere with the formation of a three-dimensional structure between these proteins. Vaccine composition characterized by.
상기 Gn 단백질이 사람 항체의 Fc 부위에 융합된 형태는, 서열번호 10의 아미노산 서열에서 그 N-말단의 DVAQAA(Asp Val Ala Gln Ala Ala) 아미노산 서열이 제외된 서열로 이루어진 것을 특징으로 하는 백신 조성물.
In paragraph 1,
The vaccine composition in which the Gn protein is fused to the Fc region of a human antibody is composed of a sequence excluding the N-terminal DVAQAA (Asp Val Ala Gln Ala Ala) amino acid sequence from the amino acid sequence of SEQ ID NO: 10 .
상기 조성물은 약학적으로 허용되는 담체를 포함하는 것을 특징으로 하는 백신 조성물.
According to claim 1,
The vaccine composition, characterized in that the composition comprises a pharmaceutically acceptable carrier.
상기 약학적으로 허용되는 담체는 희석제, 부형제, 안정화제 및 방부제로 구성된 군에서 선택된 하나 이상을 포함하는 것을 특징으로 하는 백신 조성물.
According to claim 5,
The pharmaceutically acceptable carrier is a vaccine composition, characterized in that it comprises at least one selected from the group consisting of diluents, excipients, stabilizers and preservatives.
상기 조성물은 활성성분 보조제를 추가로 포함하는 것을 특징으로 하는 백신 조성물.
According to claim 1,
The composition is a vaccine composition, characterized in that it further comprises an active ingredient adjuvant.
상기 보조제는 겔 상의 알루미늄염인 것을 특징으로 하는 백신 조성물.
According to claim 7,
The adjuvant is a vaccine composition, characterized in that the aluminum salt in the form of a gel.
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